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Hip prosthetic loosening is often difficult to detect at an early stage, and there has been uncertainty for a long time as to when the loosening occurs and thus to the basic causes. By comparing different diagnostic methods, we found that loosening is best defined as prosthetic migration and measured by radiostereometric analysis. Convincing evidence indicates that poor interlock, poor bone quality, and resorption of a necrotic bone bed may initiate loosening during or shortly after surgery; this forms the basis of the theory of early loosening. Biomechanical factors do affect the subsequent progression of loosening, which may increase subclinically during a long period of time. Eventually, the loosening may be detected on standard radiographs and may be interpreted as late loosening but should to be interpreted as late detection of loosening. The theory of early loosening explains the rapid early migration, the development of periprosthetic osteolysis and granulomas, the causality between wear and loosening, and largely the epidemiology of clinical failure of hip prostheses. Aspects discussed are definition of loosening, the pattern of early migration, the choice of migration threshold, the current understanding of loosening, a less exothermic bone cement, cemented taper-slip stems, a new exciting computed tomography-based technique for simpler implant migration studies, and research suggestions.

Background: Clinical and microbiological guidelines recommend treating infections caused by Enterobacter spp. with cefepime or carbapenems. The main objective of this study was to assess the risk of clinical failure with third generation cephalosporin (3GC) therapy compared to other β-lactams for infections caused by Enterobacter spp. Our secondary objective was to evaluate the risk of emergence of resistance during therapy. Methods: We conducted a prospective observational study in seven French hospitals over an 18-month period including all patients with a pulmonary and/or bloodstream infection due to Enterobacter spp. susceptible to 3GC. Results: Seventy-four patients were included in our study. Among them, 26 (35%) received a 3GC as a first-line treatment, and clinical improvements were observed for 13/21 (62%) of them. Four (5%) cases of emergence of 3GC resistance were observed during therapy including one in the 3GC group. 3GC therapy can be safely used as first-line therapy especially for non-severe patients suffering from pulmonary or bloodstream infections due to Enterobacter spp. Conclusions: Emergence of 3GC resistance remains a rare event, and there is a lack of evidence of the benefit of last-line antibiotics therapies.

Super bioavailable itraconazole (SBITZ) is a newer formulation of itraconazole which is recently launched in India. But there is no published clinical evidence of SBITZ in the management of dermatophytosis in Indian patients.A Real world retrospective data analysis was conducted with 346 dermatologists across India to assess the response of Indian patients with dermatophytosis who were prescribed super bioavailable itraconazole 50 mg twice a day for 4 weeks.Out of 4625 patients’ data, 2743 were included for final analysis. Mean age of patients was 36.17±12.05 years with male preponderance. Most of the patients were diagnosed as T. cruris. At the end of treatment, 51% of patients achieved complete clinical cure while 46% achieved clinical improvement (>50% symptom clearance) and 3% were labelled as clinical failure. About 70% patients achieved clearance in body surface area. Mean total symptom score (TSS) was reduced to 0.74±1.1 from 7.29±1.73 while mean BSA score was reduced from 1.96±0.83 to 0.38±0.65 (pPatients treated with super bioavailable itraconazole showed greater improvement in clearance of symptoms as well as lesions. Additionally, it showed significant improvement in naïve, recurrent and chronic patients enabling its placement in armamentarium of management of all types of dermatophytosis.

Objective: To compare the frequency of clinical failure of lingual retainers bonded with primerless flowable adhesives and conventional bonding adhesives. Study Design: Quasi experimental study. Place and Duration of Study: Department of Orthodontics, Armed Forces Institute of Dentistry Rawalpindi, from Jul 2017 to Jun 2018. Methodology: As per selection criteria, 76 patients were selected by non-probability consecutive sampling technique. Patients were divided into two groups: the conventional bonding adhesive and the primerless flowable adhesive group with 38 patients in each group. Retainers were bonded using standardized procedure with conventional bonding adhesive in one group and primerless flowable adhesive for bonding in the other group. After bonding of retainers, patients were recalled after 3 months and any bonding failures were recorded. Results: Failure rate with conventional bonding adhesive was 10.5% while on the other hand, failure with primerless flowable adhesive was 31.6% with a p-value of 0.047 which showed a statistically significant difference. Conclusion: There was a statistically significant difference of clinical failure rate of lingual retainers bonded with conventional bonding adhesive versus primerless flowable adhesive with greater failure rate of the primerless flowable adhesive.

Background Polyetheretherketone (PEEK) suture anchors are frequently used in Bankart shoulder stabilisation. This study analyzed the primary stability and revisability of PEEK anchors in-vitro in case of primary Bankart repair and revision Bankart repair after failed primary repair. Methods To simulate primary Bankart repair, 12 anchors (Arthrex PEEK PushLock® 3.5 mm) were implanted in 1, 3, 5, 7, 9 and 11 o'clock positions in cadaveric human glenoids and then cyclically tested. To simulate revision Bankart repair, 12 anchors were implanted in the same manner, over-drilled and 12 new anchors of the same diameter were implanted into the same bone socket as the primary anchors and then cyclically tested. The maximum failure loads (Fmax), system displacements, force at clinical failure and modes of failure were recorded. Results One primary anchor failed prematurely due to a technical problem. Three out of 12 revision anchors (25%) dislocated while setting the 25 N preload. The Fmax, the displacement and clinical failure of the remaining 9 revision anchors were non-significant when compared to the 11 primary repair anchors. The main mode of failure in the primary and revision Bankart surgery group was suture slippage. Anchor dislocations were observed four times in the primary and once in the revision repair groups. Conclusions Revision Bankart repair using PEEK anchors of the same diameter in a pre-existing bone socket is possible but bears high risk of premature anchor failure and can jeopardize the reconstruction. PEEK suture anchor in revision Bankart surgery should be implanted in a new bone socket if possible.

Balloon- or plug-assisted retrograde transvenous obliteration of portosystemic shunts is an effective endovascular technique for the treatment of type B bypass hepatic encephalopathy. We describe a patient who underwent balloon- and plug-assisted obliteration for a lienorenal and lienogonadal shunt, respectively. He returned with symptoms of recurrent hepatic encephalopathy two years later due to reformation of new lienorenal and lienogonadal shunts. Repeat obliteration of these new shunts was now performed using balloon and coil assistance. We describe the treatment for multiple portosystemic shunts with combined usage of vascular plug, balloon and coils depending on anatomical and technically factors. Our case also highlights that after shunt obliteration increased portal pressure may form new portosystemic collateral pathways which leads to clinical failure and may require repeat treatment.

Objective:Prescribing metrics, cost, and surrogate markers are often used to describe the value of antimicrobial stewardship (AMS) programs. However, process measures are only indirectly related to clinical outcomes and may not represent the total effect of an intervention. We determined the global impact of a multifaceted AMS initiative for hospitalized adults with common infections.Design:Single center, quasi-experimental study.Methods:Hospitalized adults with urinary, skin, and respiratory tract infections discharged from family medicine and internal medicine wards before (January 2017–June 2017) and after (January 2018–June 2018) an AMS initiative on a family medicine ward were included. A series of AMS-focused initiatives comprised the development and dissemination of: handheld prescribing tools, AMS positive feedback cases, and academic modules. We compared the effect on an ordinal end point consisting of clinical resolution, adverse drug events, and antimicrobial optimization between the preintervention and postintervention periods.Results:In total, 256 subjects were included before and after an AMS intervention. Excessive durations of therapy were reduced from 40.3% to 22% (P < .001). Patients without an optimized antimicrobial course were more likely to experience clinical failure (OR, 2.35; 95% CI, 1.17–4.72). The likelihood of a better global outcome was greater in the family medicine intervention arm (62.0%, 95% CI, 59.6–67.1) than in the preintervention family medicine arm.Conclusion:Collaborative, targeted feedback with prescribing metrics, AMS cases, and education improved global outcomes for hospitalized adults on a family medicine ward.

Fretting corrosion is one contributor to the clinical failure of modular joint arthroplasty. It is initiated by micromotion in metal junctions exposed to fluids. Omitting metal-on-metal contacts could help to reduce the corrosion risk. The coating of one metal taper partner with a ceramic-based silicon nitride (SiNx) coating might provide this separation. The aim of the study was to identify whether a SiNx coating of the male taper component influences the micromotion within a taper junction. Hip prosthesis heads made of CoCr29Mo6 (Aesculap) and Ti6Al4V (Peter Brehm) were assembled (2000 N) to SiNx-coated and uncoated stem tapers made of Ti6Al4V and CoCr29Mo6 (2×2×2 combinations, each n = 4). Consecutive sinusoidal loading representing three daily activities was applied. Contactless relative motion in six degrees of freedom was measured using six eddy-current sensors. Micromotion in the junction was determined by compensating for the elastic deformation derived from additional monoblock measurements. After pull-off, the taper surfaces were microscopically inspected. Micromotion magnitude reached up to 8.4 ± 0.8 µm during loading that represented stumbling. Ti6Al4V stems showed significantly higher micromotion than those made of CoCr29Mo6, while taper coating had no influence. Statistical differences in pull-off forces were found for none of the taper junctions. Microscopy revealed CoCr29Mo6 abrasion from the head taper surface if combined with coated stem tapers. Higher micromotion of Ti6Al4V tapers was probably caused by the lower Young’s modulus. Even in the contact areas, the coating was not damaged during loading. The mechanics of coated tapers was similar to uncoated prostheses. Thus, the separation of the two metal surfaces with the objective to reduce in vivo corrosion appears to be achievable if the coating is able to withstand in vivo conditions. However, the hard ceramic-based stem coating lead to undesirable debris from the CoCr29Mo6 heads during loading.

To evaluate the clinical success rate, along with risk factors for failure, in patients undergoing latissimus dorsi transfer for the treatment of massive, irreparable, previously failed rotator cuff tears.We performed a retrospective chart review of prospectively collected data from an institutional shoulder outcome registry. All patients who underwent latissimus dorsi transfer for previously failed rotator cuff repair between 2006 and 2013 with a minimum follow-up period of 1 year were included in the study. The indications for inclusion were large (≥2 tendons), retracted, chronic rotator cuff tears with fatty infiltration or atrophy for which prior surgical repair had failed. Preoperative and postoperative American Shoulder and Elbow Surgeons (ASES) and Simple Shoulder Test scores were collected, along with postoperative Single Assessment Numerical Evaluation scores. Complications and clinical failures (Δ in ASES score17) were recorded. Patient demographic and tear characteristics were evaluated as potential risk factors for failure.A total of 22 patients (mean age, 53 ± 6 years) were included in the study, with a mean follow-up time of 3.4 ± 1.1 years. Over 63% of patients (n = 14) reported undergoing 2 or more prior failed rotator cuff repairs. Patients undergoing latissimus dorsi transfer showed significant improvements in ASES scores (from 35.2 ± 21.9 preoperatively to 55.8 ± 22.9 postoperatively, P = .001), Simple Shoulder Test scores (from 3.5 ± 3.1 preoperatively to 5.2 ± 3.4 postoperatively, P = .002), and pain scores (from 5.9 ± 2.8 preoperatively to 4.6 ± 4.3 postoperatively, P = .002) at final follow-up. The complication rate after latissimus transfer was 27%. The rate of revision to reverse total shoulder arthroplasty was 13.6% (n = 3) after a mean of 2.7 years, and the clinical failure rate was 41% (n = 9) at final follow-up. An acromiohumeral interval of less than 7 mm (P = .04) and high-grade fatty infiltration (grade 3 or greater, P = .004) were significant preoperative risk factors for clinical failure.Latissimus dorsi tendon transfer resulted in a clinical failure rate of 41% and complication rate of 27%, with an acromiohumeral interval of less than 7 mm and high-grade fatty infiltration being associated with postoperative failure.Level IV.

To compare the clinical and epidemiological aspects associated with different predominant lineages circulating in Marseille from March 2020 to January 2021.In this single-centre retrospective cohort study, characteristics of patients infected with four different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants were documented from medical files. The outcome was the occurrence of clinical failure, defined as hospitalization (for outpatients), transfer to the intensive care unit (inpatients) and death (all).A total of 254 patients were infected with clade 20A (20AS), 85 with Marseille-1 (M1V), 190 with Marseille-4 (M4V) and 211 with N501Y (N501YV) variants. 20AS presented a bell-shaped epidemiological curve and nearly disappeared around May 2020. M1V reached a very weak peak, then disappeared after six weeks. M4V appeared in July presented an atypical wave form for 7 months. N501YV has only recently appeared. Compared with 20AS, patients infected with M1V were less likely to report dyspnoea (adjusted odds ratio (OR) 0.50, p 0.04), rhinitis (aOR 0.57, p 0.04) and to be hospitalized (aOR 0.22, p 0.002). Patients infected with M4V were more likely to report fever than those with 20AS and M1V (aOR 2.49, p 0.0001 and aOR 2.30, p 0.007, respectively) and to be hospitalized than those with M1V (aOR 4.81, p 0.003). Patients infected with N501YV reported lower rate of rhinitis (aOR 0.50, p 0.001) and anosmia (aOR 0.57, p 0.02), compared with those infected with 20AS. A lower rate of hospitalization was associated with N501YV infection compared with 20AS and M4V (aOR 0.33, p 0.0001 and aOR 0.27, p 0.0001, respectively).The four lineages have presentations that differ from one another, epidemiologically and clinically. This supports SARS-CoV-2 genomic surveillance through next-generation sequencing.

Following the high clinical failure rates of metal-on-metal total hip replacements much work has been undertaken to investigate their poor performance. So called adverse loading scenarios such as acetabular inclination and microseparation have been attributed to indicators for failure of the implants. The ISO hip simulation standards (ISO 14242:1) still rely on gravimetric and ex situ analysis, considering only the total wear during articulation. Live in situ sensing can provide valuable insight into the degradation mechanisms of metallic interfaces under such scenarios. Clinical 28 mm diameter metal-on-metal components were articulated in a full-ISO hip simulator. The bearings were subjected to increasing angles of acetabular inclination and retroversion over short-term periods of articulation. Corrosive degradation was monitored during sliding by means of an in situ three-electrode cell. Changing acetabular inclination from 30° to 50° resulted in greater cathodic shifts in OCP upon the initiation of sliding; from −50 mV to as much as −150 mV. Under anodic polarisation (0 mV vs. Ag/AgCl) the resultant currents at the initiation of sliding also increased significantly with inclination; from approximately 4–10 µA to over 120 µA. Increased retroversion of 20° also resulted in increased anodic currents of 55–60 µA. Changing the nature of articulation demonstrated increased corrosive material loss compared to a standard ISO 14242 profile. The sole use of gravimetric assessment to determine a wear rate for hip replacement bearings under simulation can therefore neglect important degradation mechanisms, such as tribocorrosive loss in devices with metal sliding interfaces.

Background: Right ventricular (RV) function plays a vital role in the prognosis of patients with chronic thromboembolic pulmonary hypertension (CTEPH). We used new machine learning (ML)-based fully automated software to quantify RV function using three-dimensional echocardiography (3DE) to predict adverse clinical outcomes in CTEPH patients.Methods: A total of 151 consecutive CTEPH patients were registered in this prospective study between April 2015 and July 2019. New ML-based methods were used for data management, and quantitative analysis of RV volume and ejection fraction (RVEF) was performed offline. RV structural and functional parameters were recorded using 3DE. CTEPH was diagnosed using right heart catheterization, and 62 patients underwent cardiac magnetic resonance to assess right heart function. Adverse clinical outcomes were defined as PH-related hospitalization with hemoptysis or increased RV failure, including conditions requiring balloon pulmonary angioplasty or pulmonary endarterectomy, as well as death.Results: The median follow-up time was 19.7 months (interquartile range, 0.5–54 months). Among the 151 CTEPH patients, 72 experienced adverse clinical outcomes. Multivariate Cox proportional-hazard analysis showed that ML-based 3DE analysis of RVEF was a predictor of adverse clinical outcomes (hazard ratio, 1.576; 95% confidence interval (CI), 1.046~2.372; P = 0.030).Conclusions: The new ML-based 3DE algorithm is a promising technique for rapid 3D quantification of RV function in CTEPH patients.

Hip arthroscopy is a reproducible and efficacious procedure for the treatment of femoroacetabular impingement syndrome (FAIS). Despite this efficacy, clinical failures are observed, clinical entities are challenging to treat, and revision hip arthroscopy may be required. The most common cause of symptom recurrence after a hip arthroscopy that leads to a revision arthroscopy is residual cam morphology as a result of inadequate femoral osteochondroplasty and restoration of head–neck offset, though several other revision etiologies including progressive chondral and labral pathologies also exist. In these cases, it is imperative to perform a comprehensive examination to identify the cause of a failed primary arthroscopy as to assess whether or not a revision hip arthroscopy procedure is indicated. When a secondary procedure is indicated, approaches may consist of revision labral repair, complete labral reconstruction, or labral augmentation depending on labral integrity. Gross instability or imaging-based evidence of microinstability may necessitate capsular augmentation or plication. If residual cam or pincer morphology is present, additional resection of the osseous abnormalities may be warranted. This review article discusses indications, the evaluation of patients with residual symptoms after primary hip arthroscopy, and the evaluation of outcomes following revision hip arthroscopy through an evidence-based discussion. We also present a case example of a revision hip arthroscopy procedure to highlight necessary intraoperative techniques during a revision hip arthroscopy.

Background: The aim of our study is to evaluate whether serum infliximab trough levels (ITL) during the early stages of treatment are predictive of long-term clinical failure in patients with axial spondyloarthritis (axSpA).Methods: Longitudinal observational study involving 81 patients with axSpA recruited from the SpA-Paz cohort and monitored during infliximab therapy. Serum ITL were measured at baseline, week 2 (W2), W6 and W12 of treatment. Disease activity was assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS) at baseline, W24 and W54, and every 6 months thereafter until therapy failure. Non-clinically important improvement was defined by ΔASDASResults: Out of the 81 patients, 45 (56%) did not achieve clinical improvement at W52. These patients had lower serum ITL at W12 compared to those who improved: ITL [median (IQR)]: 4.1(0.9-8.3) µg/ml vs 7.1(4.3-11.3)µg/ml, respectively; p=0.007). A cut-off of ITLConclusions: Serum ITL

Background The purpose of this trial was to determine whether anterior cruciate ligament reconstruction (ACLR) with anterolateral structure augmentation (ALSA) would result in better clinical outcomes in patients with a high risk of clinical failure. Methods From February 2017 to June 2018, 120 young, active adults with chronic anterior cruciate ligament injury and high risk of clinical failure were randomized. The patients were followed for >2 years, with 5 being lost to follow-up and 1 being withdrawn from the study. Clinical characteristics, operative findings, and postoperative clinical outcomes were analyzed. Results The analysis included data from 114 patients, including 95 men and 19 women with a mean age (and standard deviation) of 30.1 ± 6.7 years in the ACLR group and 30.1 ± 6.4 years in the ALSA group. The rate of clinical failure was 20.4% (11 of 54 patients) and 3.3% (2 of 60 patients) in the ACLR and ALSA groups, respectively (difference, 17.1%; 95% confidence interval [CI], 5.3% to 29.8%; p = 0.007). Significantly higher rates of return to the preinjury level of sports (48.3% versus 27.8%; difference, 20.5%; 95% CI, 2.7% to 36.6%; p = 0.024) and to a competitive level of play (63.3% versus 42.6%; difference, 22.3%; 95% CI, 4.1% to 38.8%; p = 0.027) was found in the ALSA group. Conclusions Compared with isolated ACLR, combined ACLR and ALSA resulted in a reduction in persistent rotatory laxity and higher rates of return to preinjury and competitive levels of play at 2 years of follow-up in the population studied. Our study suggests that patients with high risk of clinical failure appear to be candidates for the ALSA approach. Level of evidence Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Magnesium is an essential element that is involved in the regulation of cell growth, division and differentiation. Epidemiologic studies have demonstrated that a diet poor in magnesium is associate...

Objectives This study compared the condom failure rate, safety and acceptability of two new synthetic adhesive male condoms, Wondaleaf-Cap® (WLC) and Wondaleaf-On-Man® (WLM), with a marketed latex external condom Durex®-Together (DT). Study design We enrolled healthy married, monogamous, heterosexual condom users in a randomized controlled, cross-over, pilot trial in Malaysia. We randomized participants to six groups with different condom use-orders of the experimental WLC and WLM and control latex condom for four episodes for vaginal sex over 1 month for each condom type. We summarized the clinical and non-clinical failure rate, safety and acceptability of each condom type using descriptive statistics. We tested differences in condom failure and acceptability using generalized estimating equations and repeated measure ANOVA respectively. Results We screened 75 couples and randomized 50 eligible couples. Two couples withdrew before receiving any condom. The remaining used 576 condoms with 192 uses for each condom variant. Clinical failure rates of WLC, WLM and DT were 1.04%, 0% and 0.52%, respectively. Non-clinical failure rates of WLC, WLM and DT were 2.08%, 3.12% and 1.04%, respectively. Removal was found more painful with Wondaleaf products than the DT. Preferences of participants for WLC, WLM and DT were 33.3%, 29.2% and 25%, respectively. Overall, WLC and DT had greater acceptances among male participants than WLM. Conclusion Results of this pilot study support that use of synthetic adhesive male condoms is associated with failure rates similar to those seen with existing latex, and with greater acceptability. A larger study to ascertain non-inferiority is underway. Implications The availability of synthetic adhesive male condoms may increase the acceptability of condom use. However, removal pain and clinical performance requires further study.

Dual-mobility (DM) total hip arthroplasty (THA) systems are designed to increase stability while potentially avoiding problems associated with large femoral heads. Complications of these systems are not yet fully understood. This study aims at characterizing in vivo performance of DM hip systems and assessing modes of clinical failure.Under an institutional review board-approved implant retrieval protocol, 18 DM THA systems from 17 patients were included. Implants were graded at the head-neck junction for fretting and corrosion based on the system of Goldberg et al. Components were also macroscopically examined for different damage modes. Demographics and surgical data were collected from medical records, and radiographs were assessed for component positioning. Data were analyzed through Spearman rank-order correlation and Mann-Whitney U-tests, with α = 0.05.The average length of implantation was 13.4 months with mild to moderate fretting corrosion damage. Polyethylene (PE) liners exhibited edge deformation, scratching, and pitting damage. Metallic components exhibited burnishing and scratching damage. Summed fretting and corrosion scores were strongly correlated (ρ = 0.967, P.0001). Summed corrosion score was moderately correlated with presence of embedding on the PE liner (ρ = 0.690, P = .017). PE liner abrasion and edge deformation of the femoral stem taper were moderately positively correlated (ρ = 0.690, P = .017). Fretting and corrosion damage were not significantly correlated with patient demographics or radiographic positioning of implants. There were no differences in scores between modular and monoblock designs.These findings demonstrate that dual-mobility THA systems may be susceptible to the same fretting and corrosion damage observed in traditional modular THA systems. Future studies are needed to confirm these results and clinical significance.

Surgical treatment of patients with massive rotator cuff tears is unpredictable because of a low healing rate and high incidence of clinical failure. Arthroscopic superior capsular reconstruction has emerged as a promising technique in treating younger, active patients with massive irreparable rotator cuff tears. Superior capsular insufficiency has been theorized to be a factor in the higher failure rate for repairs of massive tears, and there have been proposals of superior capsular repair in addition to rotator cuff repair to facilitate better healing of massive rotator cuff tears. This article presents our technique of functional rotator cuff augmentation, which is concomitant superior capsular reconstruction with arthroscopic rotator cuff repair, to treat massive, atrophic rotator cuff tears. This technique is used in patients with massive rotator cuff tears and superior capsular insufficiency.

AD is a progressive neurodegenerative disorder and a leading cause of dementia in an aging population worldwide. The enormous challenge which AD possesses to global healthcare makes it as urgent as ever for the researchers to develop innovative treatment strategies to fight this disease. An in-depth analysis of the extensive available data associated with the AD is needed for a more comprehensive understanding of underlying molecular mechanisms and pathophysiological pathways associated with the onset and progression of the AD. The currently understood pathological and biochemical manifestations include cholinergic, Aβ, tau, excitotoxicity, oxidative stress, ApoE, CREB signaling pathways, insulin resistance, etc. However, these hypotheses have been criticized with several conflicting reports for their involvement in the disease progression. Several issues need to be addressed such as benefits to cost ratio with cholinesterase therapy, the dilemma of AChE selectivity over BChE, BBB permeability of peptidic BACE-1 inhibitors, hurdles related to the implementation of vaccination and immunization therapy, and clinical failure of candidates related to newly available targets. The present review provides an insight to the different molecular mechanisms involved in the development and progression of the AD and potential therapeutic strategies, enlightening perceptions into structural information of conventional and novel targets along with the successful applications of computational approaches for the design of target-specific inhibitors.

L’utilisation de dermes xenogeniques decellularises d’origine porcine (Mucoderm®) est actuellement une alternative a l’autogreffe gingivale offerte au clinicien en chirurgie parodontale. Dans une optique experimentale de recours a un materiau alternatif au tissu conjonctif autologue nous avons selectionne un cas d’augmentation de gencive keratinisee. Les resultats attendus avaient ete decevants ce qui nous a amene a poser la problematique de l’evolution in situ de cette matrice et de la realite de sa bio-integration. Nous presentons dans ce cas clinique les resultats d’une biopsie prelevee chez un patient. La biopsie pratiquee a 11 semaines dans une zone du site greffe de derme xenogenique et cliniquement juge peu concluant, montre apres coloration des lames a l’hematoxyline-eosine, la presence de nombreuses cellules inflammatoires dans le conjonctif gingival a la peripherie d’une ulceration a l’interieur de laquelle de nombreuses cellules geantes a corps etranger forment un granulome ; de meme, de tres denses fibres de collagene nouvellement formees sont presentes et qui font penser a un tissu fibrotique. Cet echec clinique relatif peut ainsi reveler la mauvaise bio-integration du materiau liee a sa structure macromoleculaire et a une mauvaise colonisation de cette matrice par les cellules tels les fibroblastes gingivaux, mais aussi par extension a une mauvaise neoangiogenese. Abstract Recently, porcine acellular dermal matrix (Mucoderm®) has become an alternative to connective tissue autografts in periodontal surgery. For the experimental purpose of using an alternative material to autologous connective tissue we selected a case of keratinized gingival augmentation. The expected results had been disappointing, which led us to ask the problem of the evolution in situ of this matrix and the reality of its bio-integration. We investigated in vivo human biopsy taken from patient who underwent xenogenic dermal transplant. Biopsy obtained at 11 weeks post-tissue transplant and stained with Hematoxylin-Eosin demonstrated the presence of numerous inflammatory cells in the connective gingival tissue at the periphery of ulceration inside of which many foreign body giant cells constitute a granuloma; similarly, newly formed collagen fibers are present, very dense and reminiscent of fibrotic tissue. This relative clinical failure can thus reveal the poor bio-integration of the material related to its macromolecular structure and poor colonization of this matrix by cells such as gingival fibroblasts, but also by extension to poor neoangiogenesis.

Background Altered pharmacokinetics in obese patients raise concerns over worse clinical outcomes. This study assessed whether obese patients receiving a β-lactam have worse clinical outcomes compared to nonobese patients and to identify if therapeutic drug monitoring may be beneficial. Methods This multicenter, retrospective cohort included hospitalized adults admitted from July 2015 to July 2017 treated with a β-lactam as definitive monotherapy against a gram-negative bacilli for ≥72 hours. Patients were excluded if there was lack of source control or if polymicrobial infections required >1 antibiotic for definitive therapy. Patients were classified based on body mass index (BMI): nonobese (BMI ≤29.9 kg/m2) and obese (BMI ≥30.0 kg/m2). The primary outcome was clinical treatment failure, and secondary outcomes were hospital length of stay, inpatient all-cause mortality, and 30-day all-cause readmission. Results There were 257 (43.6%) obese patients and 332 (56.4%) nonobese patients included. The most common infections were urinary (50.9%) and respiratory (31.4%). Definitive treatment was driven by third-generation cephalosporins (46.9%) and cefepime (44.7%). Treatment failure occurred in 131 (51%) obese patients and 109 (32.8%) nonobese patients (P, Altered pharmacokinetics in obese patients raise concerns over worse clinical outcomes. In this study, obese patients treated with β-lactams have higher rates of treatment failure and longer hospitalization periods than nonobese patients.

Clinical results of meniscal allograft transplantation (MAT) are not always consistent with graft status. This study aimed to investigate (1) the degree and pattern of mismatch between anatomic and clinical failures in MAT and (2) preoperative factors associated with the mismatch.Two hundred and ninety-eight consecutive patients who underwent primary medial or lateral MAT during 2004-2015 were reviewed. Anatomic failure was defined as an allograft showing meniscal tear involving 50% of the graft or unstable peripheral rim. Clinical failure included poor Lysholm score of 65 and any requirement for re-operations such as arthroplasty, realignment osteotomy, revision MAT, and meniscectomy (more than 50% of the graft or to the zone of meniscocapsular junction). Failure cases were categorised according to the type of failure as follows: (1) type 1, anatomic failure followed by clinical failure; (2) type 2, anatomic failure did not lead to clinical failure; and (3) type 3, clinical failure without anatomic failure. Preoperative factors including age, sex, body mass index, MAT compartment, time from previous meniscectomy, alignment, cartilage status, and accompanying procedures were analysed according to the failure type.Forty (13.4%) patients showed anatomical or clinical failure during the median (25th-75th percentile) follow-up duration of 47 (30-72) months (range 24-178 months). Eleven (3.7%) patients showed both anatomical and clinical failure (type 1 failure). Seventeen (5.7%) patients showed anatomic failure that did not lead to clinical failure (type 2 failure). Twelve (4.0%) patients failed clinically without meniscal tear ( 50% of graft) or unstable peripheral rim (type 3 failure). Comparative analyses among failure types found a significant difference in MAT compartment (p = 0.01). In particular, the incidence of type 3 failure was higher in medial than in lateral MAT (p = 0.003).A notable number of failure cases of MAT showed a mismatch between anatomic and clinical failures. Even with anatomic failure, MAT did not always lead to poor clinical scores or re-operations, whereas MAT could have poor results without substantial allograft problems. Therefore, both anatomic and clinical aspects should be considered when evaluating MAT. In particular, type 3 failure occurred more frequently in medial than in lateral MAT.III.

Antimicrobial therapy is facing a worrisome and underappreciated challenge, the phenomenon of heteroresistance (HR). HR has been gradually documented in clinically relevant pathogens (e.g. Pseudomonas aeruginosa, Staphylococcus aureus, Burkholderia spp., Acinetobacter baumannii, Klebsiella pneumoniae, Candida spp.) towards several drugs and is believed to complicate the clinical picture of chronic infections. This type of infections are typically mediated by polymicrobial biofilms, wherein microorganisms inherently display a wide range of physiological states, distinct metabolic pathways, diverging refractory levels of stress responses, and a complex network of chemical signals exchange. This review aims to provide an overview on the relevance, prevalence, and implications of HR in clinical settings. Firstly, related terminologies (e.g. resistance, tolerance, persistence), sometimes misunderstood and overlapped, were clarified. Factors generating misleading HR definitions were also uncovered. Secondly, the recent HR incidences reported in clinically relevant pathogens towards different antimicrobials were annotated. The potential mechanisms underlying such occurrences were further elucidated. Finally, the link between HR and biofilms was discussed. The focus was to recognize the presence of heterogeneous levels of resistance within most biofilms, as well as the relevance of polymicrobial biofilms in chronic infectious diseases and their role in resistance spreading. These topics were subject of a critical appraisal, gaining insights into the ascending clinical implications of HR in antimicrobial resistance spreading, which could ultimately help designing effective therapeutic options., This work was supported by the Portuguese Foundation for Science Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2020 unit BioTecNorte operation [NORTE-01-0145-FEDER-000004] funded by the European Regional Development Fund under the scope of Norte2020–Programa Operacional Regional do Norte. The authors also acknowledge COMPETE2020 FCT for the project POCI-01-0145-FEDER-029,841 and for the Scientific Employment Stimulus 2017 grant [CEECIND/01507/2017] (A. M. Sousa)., info:eu-repo/semantics/publishedVersion

Background Scrub typhus is typically associated with a rapid defervescence and clinical improvement within 48 h of initiation of appropriate antibiotics. But increasing reports of resistance to anti-rickettsial medications in scrub typhus are being reported in the literature. Methods This is a retrospective observational study of children up to the age of 14 years admitted between July 2017 and March 2020, to a private medical college hospital in southern part of India. The aim of this study was to compare the clinical response to antibiotic therapy with doxycycline and azithromycin in pediatric scrub typhus infection. Results One hundred thirty-eight children with scrub typhus infection were included for analysis. The median fever control time (h) was 12 (IQR = 6–29) and 24 (IQR = 10–52) with doxycycline and azithromycin respectively (p Conclusion There has been a significant delayed clinical response to azithromycin in the treatment of scrub typhus in India, when compared to doxycycline. Hence it is preferable to use doxycycline as the first line of antibiotic for undifferentiated fever in scrub typhus endemic areas. Lay summary This retrospective study aims to compare the clinical response to doxycycline or azithromycin in the treatment of scrub typhus infection in children. The median fever control time, clinical failure rate and the proportion of children with rapid defervescence of fever within 48 h were significantly superior with doxycycline as compared to azithromycin. The findings of this study and those of similar studies in India represent a spectrum of delayed clinical response of Orientia tsutsugamushi to azithromycin as compared to doxycycline in this region.

BackgroundDespite the increase in the number of people accessing antiretroviral therapy (ART), there is limited data regarding treatment failure and its related factors among HIV-positive individuals enrolled in HIV care in resource-poor settings. This review aimed to identify factors associated with antiretroviral treatment failure among individuals living with HIV on ART in resource-poor settings.MethodsWe conducted a comprehensive search on MEDLINE (PubMed), Excerpta Medica Database (EMBASE), Cochrane Central Register of Controlled Trials (CENTRAL), World Health Organization’s (WHO’s) library database, and Latin American and Caribbean Health Sciences Literature (LILACS). We included observational studies (cohort, case-control, and cross-sectional studies) where adolescents and adults living with HIV were on antiretroviral treatment regardless of the ART regimen. The primary outcomes of interest were immunological, virological, and clinical failure. Some of the secondary outcomes were mm3opportunistic infections, WHO clinical stage, and socio-demographic factors. We screened titles, abstracts, and the full texts of relevant articles in duplicate. Disagreements were resolved by consensus. We analyzed the data by doing a meta-analysis to pool the results for each outcome of interest.ResultsAntiretroviral failure was nearly 6 times higher among patients who had poor adherence to treatment as compared to patients with a good treatment adherence (OR = 5.90, 95% CI 3.50, 9.94, moderate strength of evidence). The likelihood of the treatment failure was almost 5 times higher among patients with CD4 < 200 cells/mm3compared to those with CD4 ≥ 200 CD4 cells/mm3(OR = 4.82, 95% CI 2.44, 9.52, low strength of evidence). This result shows that poor adherence and CD4 count below < 200 cells/mm3are significantly associated with treatment failure among HIV-positive patients on ART in a resource-limited setting.ConclusionThis review highlights that low CD4 counts and poor adherence to ART were associated to ART treatment failure. There is a need for healthcare workers and HIV program implementers to focus on patients who have these characteristics in order to prevent ART treatment failure.Systematic review registrationThe systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO), registration number: 2019 CRD42019136538.

Background Natalizumab is a very effective treatment of multiple sclerosis (MS). Failure is rare and should lead to consider some specific etiologies. The purpose of our study was to describe causes of subacute neurological events under natalizumab. Methods Observational single-center retrospective study in the MS expert center of Lyon, France. Inclusion criteria: any patient with definite MS who received at least three infusions of natalizumab between April 2007 and February 2017. Clinical data were extracted from the Lyon EDMUS/OFSEP database. Events of interest: occurrence of a subacute neurological deficit, characterized by new clinical symptoms. We excluded pseudo-relapses and progression. Findings A subacute neurological deficit occurred in 35 cases, for 607 patients treated with natalizumab. Ten patients presented natalizumab antibodies, nine had progressive multifocal leukoencephalopathy (PML), five presented an isolated subacute neurological deficit and two had AQP4 antibodies. No myelin oligodendrocyte glycoprotein (MOG) antibodies were found. Interpretation The occurrence of an acute or subacute neurological deficit with natalizumab is rarely a MS relapse and should lead systematically to explore some important alternate etiologies, eliminating PML first.

In this Viewpoint, I argue that our view of antibacterial discovery, development, and commercial potential requires a balance between innovation and clinical utility. I suggest that important new clinical utility may be more important to value than whether the compound in question belongs to a novel chemical class or attacks a novel antibacterial target. Novelty in this regard may increase the risk of scientific or clinical failure. So-called nontraditional approaches to antibacterial therapy are often innovative. The attendant challenges depend on whether the compound can be a stand-alone therapy, part of a fixed-dose combination, or whether it is adjunctive to standard therapy. Suitability for pharmacokinetic-pharmacodynamic studies and antimicrobial susceptibility testing is also an important consideration.

Patients with a greater risk of recurrent instability and inferior clinical outcomes following a primary Latarjet procedure can be preoperatively identified on the basis of clinical, radiographic, and demographic criteria. The purpose of this study was to identify risk factors influencing the rates of recurrent anterior glenohumeral instability and clinical failure following a primary Latarjet procedure.All patients who underwent a primary Latarjet procedure were prospectively enrolled and evaluated. The Western Ontario Shoulder Instability Index (WOSI) and Single Assessment Numeric Evaluation (SANE) outcome scores were collected at a minimum 5-year follow-up along with evidence of recurrent instability. Recurrent instability (recurrent subluxation or dislocation) was considered as a failure. Clinical failure was defined as a postoperative WOSI score of ≥630 points (≤70% normal) or a SANE score of ≤70 points.From 2004 to 2014, 344 patients (358 shoulders) with a mean age of 30.6 years (range, 16 to 68 years) were enrolled and had a mean follow-up time of 75 months (range, 61 to 89 months). The median postoperative WOSI score was 265 points (range, 0 to 1,100 points), and the median SANE score was 88 points (range, 50 to 100 points). Recurrence occurred in 17 shoulders (4.7%), 5 with dislocation and 12 with subluxation; and 28 (8.2%) of 341 shoulders without recurrent instability were clinical failures following a Latarjet procedure. The risk factors for recurrence included atraumatic dislocation (odds ratio [OR], 4.6; p0.01) and bilateral instability (OR, 4.0; p = 0.01), whereas the risk factors for clinical failure (WOSI score of ≥630 points or SANE score of ≤70 points) were female sex (OR, 2.8; p0.01) and bilateral instability (OR, 4.6; p = 0.01).Outcomes at a mean of6 years following a primary Latarjet procedure for anterior shoulder instability were very good, with an overall recurrence rate of 4.7%. An additional 8.2% of cases were defined as clinical failures. Patients with an atraumatic mechanism of primary dislocation, bilateral instability, and female sex were identified to be at a greater risk of recurrence or clinical failure. Although additional work is necessary, patients with capsuloligamentous laxity, relatively atraumatic instability history, bilateral instability, and female sex may be preoperatively identified as having a higher risk of treatment failure after a primary Latarjet procedure.Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Skin and soft tissue abscesses are commonly treated in emergency departments (ED). The use of bedside ultrasound may improve patient outcomes. The primary objective of this study was to examine the relationship between ultrasound use and risk of treatment failure in ED patients treated for abscesses.In this multi-center observational study, we reviewed medical records of adult patients evaluated for abscesses. Demographics, infection characteristics, treatments rendered, use of ultrasound (for diagnosis and/or treatment) and follow-up data were collected from electronic medical record review. Treatment failure, the primary outcome, was defined as any surgical intervention after the initial ED visit. Multivariable logistic regression tested whether incision and drainage utilizing ultrasound was associated with reduced treatment failure.We identified 609 patients diagnosed with abscesses over a 22-month period. Of them 75% were treated with incision and drainage, 55% had an ultrasound and 15% failed treatment. Multi-variable analysis demonstrated an 8% probability of failure with ultrasound plus incision and drainage, 14% with blind incision and drainage and 25% without incision and drainage. Individuals with incision and drainage performed were 50% less likely to fail treatment (RR 0.53, 95%CI 0.35-0.81) and 70% less likely to fail treatment (RR 0.30, 95%CI 0.18-0.51) with ultrasound and incision and drainage.The use of ultrasound in diagnosing and or/treating patients with abscesses in the ED is associated with decreased treatment failure risk when utilized with incision and drainage. Consideration of ultrasound use in other studies which assess treatment methods in relation to patient outcomes may be warranted.RéSUMé : OBJECTIF: Les abcès de la peau et des tissus mous sont couramment traités dans les services d'urgence (SU). L'utilisation de l'échographie au chevet du patient peut améliorer les résultats des patients. L'objectif principal de cette étude était d'examiner la relation entre l'utilisation de l'échographie et le risque d'échec du traitement chez les patients des urgences traités pour des abcès. MéTHODES: Dans cette étude d’observation multicentrique, nous avons examiné les dossiers médicaux des patients adultes évalués pour les abcès. Les données démographiques, les caractéristiques de l'infection, les traitements rendus, l'utilisation de l'échographie (pour le diagnostic et/ou le traitement) et les données de suivi ont été recueillies à partir de l'examen des dossiers médicaux électroniques. L'échec du traitement, le critère de jugement principal, a été défini comme toute intervention chirurgicale après la visite initiale au service d'urgence. Une régression logistique multivariable a permis de vérifier si l'incision et le drainage par ultrasons étaient associés à une réduction de l'échec du traitement. RéSULTATS: Nous avons identifié 609 patients diagnostiqués avec des abcès sur une période de 22 mois. Parmi eux, 75 % ont été traités par incision et drainage, 55% ont eu une échographie et 15 % ont échoué le traitement. L'analyse multivariée a démontré une probabilité d'échec de 8 % avec échographie plus incision et drainage, 14 % avec incision et drainage aveugle et 25 % sans incision et drainage. Les personnes chez qui l'on a pratiqué une incision et un drainage avaient 50 % moins de risques d'échouer le traitement (RR 0,53, 95 % IC 0,35-0,81) et 70 % moins de risques d'échouer le traitement (RR 0,30, 95 % IC 0,18-0,51) avec l'échographie et l'incision et le drainage. CONCLUSIONS: L'utilisation de l'échographie pour le diagnostic et/ou le traitement des patients atteints d'abcès aux urgences est associée à une diminution du risque d'échec du traitement lorsqu'elle est utilisée avec l'incision et le drainage. Il peut être justifié d'envisager l'utilisation de l'échographie dans d'autres études qui évaluent les méthodes de traitement en fonction des résultats pour les patients.

Background The study was to evaluate initial antimicrobial regimen and clinical outcomes and to explore risk factors for clinical failure (CF) in elderly patients with community-acquired pneumonia (CAP). Methods 3011 hospitalized elderly patients were enrolled from 13 national teaching hospitals between January 1, 2014 and December 31, 2014 initiated by the CAP-China network. Risk factors for CF were screened by multivariable logistic regression analysis. Results The incidence of CF in elderly CAP patients was 13.1%. CF patients were older, longer hospital stays and higher treatment costs than clinical success (CS) patients. The CF patients were more prone to present hyperglycemia, hyponatremia, hypoproteinemia, pleural effusion, respiratory failure and cardiovascular events. Inappropriate initial antimicrobial regimens in CF group were significantly higher than CS group. Undertreatment, CURB-65, PH 2/FiO2 10,000/mm3, pleural effusion and congestive heart failure were independent risk factors for CF in multivariable logistic regression analysis. Male and bronchiectasis were protective factors. Conclusions Discordant therapy was a cause of CF. Early accurate detection and management of prevention to potential causes is likely to improve clinical outcomes in elderly patients CAP. Trial registration A Retrospective Study on Hospitalized Patients With Community-acquired Pneumonia in China (CAP-China) (RSCAP-China), NCT02489578. Registered 16 March 2015, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0005E5S&selectaction=Edit&uid=U0000GWC&ts=2&cx=1bnotb

Background The high rate of clinical failure of prosthetic arteriovenous grafts continues to suggest the need for novel tissue-engineered vascular grafts. We tested the hypothesis that the decellularized rat jugular vein could be successfully used as a conduit and that it would support reendothelialization as well as adaptation to the arterial environment. Materials and methods Autologous (control) or heterologous decellularized jugular vein (1 cm length, 1 mm diameter) was sewn between the inferior vena cava and aorta as an arteriovenous graft in Wistar rats. Rats were sacrificed on postoperative day 21 for examination. Results All rats survived, and grafts had 100% patency in both the control and decellularized groups. Both control and decellularized jugular vein grafts showed similar rates of reendothelialization, smooth muscle cell deposition, macrophage infiltration, and cell turnover. The outflow veins distal to the grafts showed similar adaptation to the arteriovenous flow. Both CD34, CD90 and nestin positive cells, as well as M1-type and M2-type macrophages accumulated around the graft. Conclusions This model shows that decellularized vein can be successfully used as an arteriovenous graft between the rat aorta and the inferior vena cava. Several types of cells, including progenitor cells and macrophages, are present in the host response to these grafts in this model. This model can be used to test the application of arteriovenous grafts before conducting large animal experiments.

Although many clinical reports have shown high rates of clinical success associated with fixed dental restorations made of traditional zirconium-dioxide (zirconia), clinical failure due to improper design aiming to achieve high strength and optimal aesthetics, still occurs. Previous clinical and laboratory studies indicated that veneering porcelain and the connector represent the weak parts of the fully-veneered zirconia restorations where failure may occur. Although the clinical performance of such restorations has recently been reported to be comparable to metal-ceramic restorations, more improvements in design are still required. Restorations with monolithic design made of modified translucent zirconia materials offer an excellent solution for these clinical problems. One of the advantages of monolithic restoration is that such restorations can be prepared without the weak veneering material. Thus, this restoration design has a much higher load-bearing capacity compared to the veneered restorations since it provides additional space for the high-strength zirconia material. With regard to strength and aesthetics, the translucency of the former generation of monolithic translucent zirconia, which comes with equivalent mechanical properties to traditional zirconia, is insufficient. Recently, monolithic zirconia with high translucent properties was developed for highly aesthetic clinical uses. These new systems of translucent zirconia materials have limited capacity in terms of fracture strength and fracture toughness properties. Further, earlier studies have shown doubtful aging stability for these materials. Maintaining well-known strength properties of zirconia restorations while providing high aesthetic outcome is the ultimate goal for dental restorations such as single crowns (SCs) and fixed dental prostheses (FDPs). The optimum design for restorations made of the former generation of translucent zirconia could help to prevent the risks associated with bilayered restorations and overcome the limitations of high-translucent monolithic restorations. Based on clinical needs and previous clinical observations, the overall aim of this thesis was to evaluate translucent zirconia restorations regarding the effect of design modifications, used to enhance the aesthetics, on fracture resistance.In the first three studies, I, II, and III, all the SCs and the FDPs were artificially aged and loaded to fracture. Fracture mode analysis in the different studies was performed visually and microscopically. In study I, fracture strength and fracture mode of veneered translucent zirconia SCs designed with different porcelain layer thicknesses were evaluated. The outcomes showed that translucent zirconia SCs can be veneered with minimal thickness layer of 0.5 mm porcelain without showing significantly reduced fracture strength compared to traditionally veneered (1.0-2.0 mm) SCs. Fracture strength of micro-veneered SCs with a layer of porcelain (0.3 mm) is lower than that of traditionally veneered SCs but still within range of what may be considered clinically sufficient. Porcelain layers of 2.0 mm or thicker should be used only where the expected loads are low. All the SCs in groups 2.5 and 2.0 and more than 80% of the SCs in groups 1.0, 0.8 and 0.5 showed cohesive fracture mode. Conversely, there were significantly (p≤0.05) more complete fractures in group 0.3 compared to all other groups.Study II described different designs of partially veneered monolithic (semi-monolithic) SCs made of translucent zirconia and evaluated the effect of those designs on fracture resistance and fracture mode of SCs made of two generations of translucent zirconia materials. The results demonstrated that translucent and high-translucent zirconia SCs might be used in combination with a 0.3 mm micro-coating porcelain layer with semi-monolithic design to enhance the aesthetic properties of restorations without significantly decreasing fracture resistance of the SCs. If a 0.5 mm porcelain layer is needed for a semi-monolithic SCs, wave design or cap design might be used to increase fracture resistance. The SCs made of translucent zirconia showed higher fracture loads compared to those made of high-translucent zirconia, regardless of design. All monolithic SCs, semi-monolithic SCs with 0.3 mm buccal veneer (100%), and all but one of semi-monolithic SCs with cap design (95%) showed complete fractures. Semi-monolithic SCs with wave design and semi-monolithic SCs with a 0.5 mm buccal veneer showed (70% and 55%, respectively) cohesive veneer fractures.Study III investigated the load-bearing capacity and failure mode of monolithic zirconia FDPs with different connector designs gained by using different embrasure shaping methods. The results showed that sharp embrasures and interproximal separations made with diamond discs significantly decrease the load-bearing capacity of monolithic zirconia FDPs compared to monolithic FDPs made with blunt embrasures (p

Objectives: To analyze the clinical and economic burden of community-acquired (CA) or community-onset healthcare-associated (COHCA) multidrug-resistant (MDR) infections requiring hospitalization. Methods: Case-control study. Adults admitted with CA or COHCA MDR infections were considered cases, while those admitted in the same period with non-MDR infections were controls. The matching criteria were source of infection and/or microorganism. Primary outcome was 30-day clinical failure. Secondary outcomes were 90-day and 1-year mortality, hospitalization costs and resource consumption. Results: 194 patients (97 cases and 97 controls) were included. Multivariate analysis identified age (odds ratio [OR], 1.07, 95% confidence interval [CI], 1.01-1.14) and SOFA score (OR, 1.45, CI95%, 1.15-1.84) as independent predictors of 30-day clinical failure. Age (hazard ratio [HR] 1.09, 95%CI, 1.03-1.16) was the only factor associated with 90-day mortality, whereas age (HR 1.06, 95%CI, 1.03-1.09) and Charlson Index (HR 1.2, 95%CI, 1.07-1.34) were associated with 1-year mortality. MDR group showed longer hospitalization (p

Arthroscopic partial meniscectomy (APM) continues to be the popular treatment for meniscal tears, but recent randomized controlled trials have questioned its efficacy. To provide more evidence-based criteria for patient selection, we undertook this study to identify prognostic factors associated with clinical failure after APM for medial meniscus tears.Medical records of 160 patients followed up for at least 5 years after APM for medial meniscal tears were retrospectively reviewed. Demographic data (age, sex, and body mass index), radiographic variables (Kellgren-Lawrence [K-L] grade and hip-knee-ankle [HKA] angle), and clinical scores (International Knee Documentation Committee score, Tegner activity scale score, Lysholm score, and Knee injury and Osteoarthritis Outcome Score) were recorded. Clinical failure was defined as the need for an additional surgical procedure (arthroscopy, osteotomy, or arthroplasty) or the presence of intolerable pain. Survivorship analysis with clinical failure as an end point was performed using Kaplan-Meier survival curves. Factors related to clinical failure were analyzed using a Cox proportional hazard model. Cutoff values were determined using areas under receiver operating characteristic (ROC) curves. Radiographic progression of osteoarthritis was analyzed using the chi-square test, and serial changes of clinical scores were analyzed using a linear mixed model.Clinical success rates were 95.7% at 5 years, 75.6% at 10 years, and 46.3% at 15 years. Age, HKA angle, and K-L grade (The poor prognostic factors found to be related to clinical failure after APM for a medial meniscal tear were patient age (≥ 50 years), preoperative K-L grade (≥ grade 2), and preoperative HKA angle (≥ varus 5.5°).

Background Although transarterial embolization (TAE) can powerfully control postpartum hemorrhage (PPH), clinical failure of TAE is not uncommon. Purpose To discover whether any parameters could predict timely clinical failure of TAE, then whether a supplementary intervention could be promptly initiated. Material and Methods We retrospectively analyzed 118 TAE procedures in 113 patients with PPH performed at our institution between January 2012 and May 2015. The patients were divided into the following groups: clinically successful TAE and failed TAE. Successful TAE was defined as obviation of supplementary embolization or surgical intervention for hemostasis. Gestational conditions, angiographic factors, maternal vital signs, and laboratory data were compared between the two groups. Results In total, 100 (84.8%) TAEs were clinically successful. Multivariate logistic regression analyses revealed independent risk factors of TAE clinical failure, including the requirement for augmented embolic agents, placental retention, and international normalized ratio > 1.3 ( P = 0.009, 0.001, and 0.005, respectively). The post-TAE shock index was significantly associated with TAE failure, using a cut-off value of 0.8. Conclusion The discovered independent risk factors of TAE clinical failure existed before or during the TAE procedure and could not reflect the post-TAE conditions. Although the post-TAE shock index was not an independent factor, it reflected the conditions after TAE and could indicate TAE clinical failure timely.

The availability of monoclonal antibodies has revolutionized the treatment of an increasingly broad spectrum of diseases. Inflammatory diseases are among those most widely treated with protein-based therapeutics, termed biologics. Following the first large-scale clinical trials with monoclonal antibodies performed in the 1990s by rheumatologists and clinical immunologists, the approval of these agents for use in daily clinical practice led to substantial progress in the treatment of rheumatic diseases. Despite this progress, however, only a proportion of patients achieve a long-term clinical response. Data on the use of agents blocking TNF, which were among the first biologics introduced into clinical practice, provide ample evidence of primary and secondary treatment inefficacy in patients with rheumatoid arthritis (RA). Important issues relevant to primary and secondary failure of these agents in RA include immunogenicity, methodological problems for the detection of antidrug antibodies and trough drug levels, and the implications for treatment strategies. Although there is no strong evidence to support the routine estimation of antidrug antibodies or serum trough levels during anti-TNF therapy, these assessments might be helpful in a few clinical situations; in particular, they might guide decisions on switching the therapeutic biologic in certain instances of secondary clinical failure.

PURPOSE The aim of this study was to perform a comprehensive biomechanical examination of frequently applied femoral cortical suspension devices, comparing the properties of both fixed and adjustable fixation mechanisms. It was hypothesized that adjustable loop devices demonstrate less consistent fixation properties with increased variability compared to fixed loop devices. METHODS Nine frequently applied fixation button types were tested, six adjustable and three rigid loop devices. Six samples of each device type were purchased. Each device was installed in a servo-hydraulic mechanical testing machine, running a 2000 cycle loading protocol at force increments between 50 and 500 N. Irreversible displacement in mm was measured for all of the tested samples of each implant. Ultimately, maximum load to failure was applied and measured in Nm. An irreversible displacement of 3 mm was considered failure of the implant. RESULTS Three of the six adjustable devices (GraftMax™, TightRope® ToggleLoc™) demonstrated a median displacement above the threshold of clinical failure before completion of the cycles. All adjustable loop devices showed a wide intragroup variation in terms of irreversible displacement, compared to fixed-loop devices. Fixed-loop devices provided consistent reproducible results with narrow ranges and significantly lower irreversible displacement (p

Background Acute otitis media(AOM) is the most common indication for antibiotics in children. The primary pathogens that cause AOM have changed since the introduction of the pneumococcal conjugate vaccine(PCV). The clinical failure rate of amoxicillin for treatment of AOM post-PCV is unknown.We aimed to determine the clinical failure rate of amoxicillin for the treatment of uncomplicated AOM in children. Organisms identified on culture and amoxicillin treatment failure from nasopharyngeal specimens of children age 6-35 months with uncomplicated acute otitis media at Denver Health, Denver, CO from April 2019-March 2020. Methods Children age 6-35 months seen at Denver Health, Denver, CO with uncomplicated AOM and prescribed amoxicillin were prospectively enrolled. An interim analysis of patients enrolled from April 2019-March 2020 was completed. Patients completed surveys that included the AOM-SOS©(UPMC, Pittsburgh, PA) at enrollment, days 5, 14, and 30 and had chart abstraction completed. Treatment failure was defined as: (1) requiring a new antibiotic within 14 days; (2) AOM-SOS© score on day 5 or 14 not improved by a relative reduction of ≥ 55% from baseline. Recurrence was defined as requiring a new antibiotic within 15-30 days. Nasopharyngeal swabs were obtained and bacterial culture was completed. Results In total,110 patients were enrolled. Rates of treatment failure defined by AOM-SOS© were 28.4%(37; 95%CI:25.5-33.6%) at 5 days and 15.5%(27; 95%CI:17.5-24.5%) at 14 days. However, only 4.5%(5; 95%CI:2.0-4.5%) required a new antibiotic. Recurrence occurred in 5.5% (6, 95%CI:2.5-5.5%) of patients. Of patients who had not received antibiotics before enrollment(82), culture yielded no organism in 17.0%, one organism in 42.7%, and multiple organisms in 40.0% (Table). M.catarrhalis was the most frequently identified organism (53.7% of children). Of H.influenzae isolates 52.9% (9/17) produced beta-lactamase, resulting in no treatment failures or recurrences requiring a new antibiotic. Failure rates were similar between organisms. Conclusion Despite the change in otopathogen prevalence post-PCV, preliminary data suggest that while early subjective treatment failure was common, the 14 day treatment failure and 30 day recurrence rates was low when measured by need for a new antibiotic. Failure was low even among patients with organisms that would not be expected to be treated successfully with amoxicillin, such as those with beta-lactamase producing H.influenzae and M.catarrhalis. Disclosures Samuel Dominguez, MD, PhD, BioFire (Consultant, Research Grant or Support)

An important goal of biomedical research is to translate basic research findings into useful medical advances. In the field of neuropharmacology this requires understanding disease mechanisms as well as the effects of drugs and other compounds on neuronal function. Our hope is that this information will result in new or improved treatment for CNS disease. Despite great progress in our understanding of the structure and functions of the CNS, the discovery of new drugs and their clinical development for many CNS disorders has been problematic. As a result, CNS drug discovery and development programs have been subjected to significant cutbacks and eliminations over the last decade. While there has been recent resurgence of interest in CNS targets, these past changes in priority of the pharmaceutical and biotech industries reflect several well-documented realities. CNS drugs in general have higher failure rates than non-CNS drugs, both preclinically and clinically, and in some areas, such as the major neurodegenerative diseases, the clinical failure rate for disease-modifying treatments has been 100%. The development times for CNS drugs are significantly longer for those drugs that are approved, and post-development regulatory review is longer. In this introduction we review some of the reasons for failure, delineating both scientific and technical realities, some unique to the CNS, that have contributed to this. We will focus on major neurodegenerative disorders, which affect millions, attract most of the headlines, and yet have witnessed the fewest successes. We will suggest some changes that, when coupled with the approaches discussed in the rest of this special volume, may improve outcomes in future CNS-targeted drug discovery and development efforts. This article is part of the Special Issue entitled "Beyond small molecules for neurological disorders".

Anterior cruciate ligament (ACL) injury is the most common ligament injury in the knee, and progressive instability and disability may develop in a significant number of patients. The incidence of ACL reconstruction is rapidly increasing, as is the number of failures. Although ACL reconstruction is a common procedure, less than satisfactory outcomes have been reported to occur in up to 25% of patients. The reasons for clinical failure after ACL reconstruction are numerous but can be broadly separated into 3 categories: technical, biological, and mechanical failures. It is generally thought that poor tunnel positioning (especially the femoral tunnel) is the most common technical error. Revision ACL reconstruction can be performed in 1 or 2 stages. The decision to perform a multistage approach is based on the position and size of the original tunnels. The varied success rates and associated advantages and disadvantages of each method have resulted in controversy as to the best treatment for revision ACL surgery. We describe our preferred operative technique to remove a fractured nitinol synthetic ACL graft and manage single-stage revision ACL reconstruction without bone grafting.

Background The purpose of the current study was to evaluate the clinical and functional outcomes of ACL reconstruction with tibialis anterior allograft using the anatomic anteromedial portal approach and aperture sheath and screw fixation. Methods We evaluated primary ACL reconstructions with tibialis anterior allograft using an anatomic anteromedial portal approach performed at our institution between January 2011 and February 2014. Patients with a minimum of two years of follow-up were contacted and brought back for a complete physical examination of the knee. A KT-1000 arthrometer was used to measure anterior tibial translation in both knees. Clinical outcome scores were generated using validated outcome measures. Results Forty-five patients with a mean age of 43.9 years were available for complete follow-up at a mean of 30.8 months. Of the 45 patients who came in for follow-up, two were found to have a clinical failure/ruptured graft (4.4%). Significant improvements were noted to be present compared to baseline values for all assessed clinical outcome measurements. KT-1000 arthrometer measures demonstrated a mean (± standard deviation) of 0.26 ± 1.11 mm side to side difference compared to the contralateral side with maximum manual stress applied. Conclusions Our data demonstrating significant improvements in clinical outcome assessments coupled with excellent KT-1000 arthrometer values and a low rate of clinical failure supports the use of tibialis anterior allografts with an anteromedial portal surgical approach in ACL reconstruction. This improvement in results may be related to more accurate anatomic tunnel placement via AMP drilling and improved graft fixation methods.

Therapeutic drug monitoring (TDM) has been recommended in guidelines for patients receiving posaconazole oral suspension, but its utility in patients receiving posaconazole tablet, which has an improved bioavailability, remains unclear. We used state transition models with first-order Monte Carlo microsimulation to re-examine the posaconazole exposure-response relationships reported in two phase III clinical trials (prophylaxis with posaconazole oral suspension, models 1 and 2) and a third multicenter observational TDM study (model 3). We simulated the impact of TDM-guided interventions to improve initial average posaconazole concentrations (C(avg)) to reduce clinical failure (in models 1 and 2) and breakthrough invasive fungal disease (bIFD) in model 3. Simulations were then repeated using posaconazole tablet C(avg) distributions in place of the oral suspension formulation. In all three models with posaconazole oral suspension, TDM interventions associated with maximal improvement in posaconazole C(avg) reduced absolute rates of subtherapeutic exposures (C(avg) < 700 ng/ml) by 25% to 49%. Predicted reductions in absolute clinical failure rates were 11% in model 1 and 6.5% in model 2 and a 12.6% reduction in bIFD in model 3. With the tablet formulation, maximally effective TDM interventions reduced subtherapeutic exposures by approximately 5% in all three models and absolute clinical failure rates by 3.9% in model 1 and 1.6% in model 2; there was a 1.6% reduction in bIFD in model 3. Our modeling suggests that routine TDM during prophylaxis with posaconazole tablets may have limited clinical utility unless populations with higher prevalence (>10%) of subtherapeutic exposures can be identified based on clinical risk factors.