Lower anxiety level to perform movements after revision anterior cruciate ligament reconstruction with lateral extra-articular tenodesis compared to without lateral extra-articular tenodesis.

PURPOSE: To evaluate the anxiety level to perform movements in patients after revision anterior cruciate ligament reconstruction (ACLR) combined with lateral extra-articular tenodesis (LET) compared to patients after revision ACLR without LET. METHODS: Ninety patients who underwent revision ACLR with ipsilateral bone-patellar tendon-bone autograft and with a minimum of 12 months follow-up were included in this study. Patients were divided into two groups: patients who received revision ACLR in combination with LET (revision ACLR_LET group; mean follow-up: 29.4 months, range: 12-80 months), and patients who received revision ACLR without LET (revision ACLR group; mean follow-up: 61.1 months, range: 22-192 months). All patients filled in a questionnaire about anxiety level related to physical activity and sports, the Knee injury and Osteoarthritis Outcome Score (KOOS), the International Knee Documentation Committee subjective form (IKDCsubjective), and the Tegner Activity Score. RESULTS: Patients in the revision ACLR_LET group had a significantly lower anxiety level to perform movements than patients in the revision ACLR group (p < 0.05). No significant differences were found in KOOS, IKDCsubjective, and Tegner Activity Scores. CONCLUSIONS: Patients who received LET in addition to revision ACLR have a lower anxiety level to perform movements than patients with revision ACLR alone, despite non-different subjective functional outcomes. STUDY DESIGN: Retrospective cohort study, Level of evidence: III.

Teleconsulting in wound care: Connecting the primary care to the wound specialist reduces unnecessary referrals.

In the Netherlands the primary care (General Practitioner or homecare nurse) encounter a variety of wounds ranging from traumatic to diabetic foot ulcers. According to a recent study 82.4% of the patients with a wound can be treated in a primary setting with the GP as medical supervisor. The remaining 17.6% of patients need more extensive care including advice by a specialised doctor, diagnosis and treatment. Prompt analyses and treatment of underlying causes by specialised doctors in a multidisciplinary setting is necessary for treating patients with complicated wound. This article describes the impact of Electronic Health Consultation on all wounds treated in the primary care. And describes the effect on the duration until referral to the hospital and the influence on the amount of unnecessary referrals to the hospital. All data was collected prospectively from June 2020 until October 2021. The study involved a process where primary care could seek advice from a Wound Physician at the Alrijne Wound Centre through a specialised Electronic Health Consultation. A total of 118 patients were analysed. 41/118 (34.7%) patients required a physical consultation with analysis and treatment in the hospital, after teleconsultation. The remaining 77/118 (65.3%) could be treated in primary care after Electronic Health Consultation. The mean duration of wound existence until Electronic Health Consultation was 39.3 days (range 5-271, SD: 38.5). 3/41 (7.3%) of the referrals were unnecessary. Electronic Health Consultation serves as a valuable and efficient tool for enhancing wound care, ultimately contributing to improved patient management and resource allocation within the healthcare system. This article describes the impact of Electronic Health Consultation on all wounds treated in the primary care and the influence on the duration until referral to the hospital and the influence on the amount of unnecessary referrals to the hospital.

R-miniCHOP versus R-CHOP in elderly patients with diffuse large B-cell lymphoma: A propensity matched population-based study.

For elderly frail patients with diffuse large B-cell lymphoma (DLBCL), an attenuated chemo-immunotherapy strategy of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-miniCHOP) was introduced as a treatment option as from 2014 onward in the Netherlands. Although R-miniCHOP is more tolerable, reduction of chemotherapy could negatively affect survival compared to R-CHOP. The aim of this analysis was to assess survival of patients treated with R-miniCHOP compared to R-CHOP. DLBCL patients ≥65 years, newly diagnosed in 2014-2020, who received ≥1 cycle of R-miniCHOP or R-CHOP were identified in the Netherlands Cancer Registry, with survival follow-up through 2022. Patients were propensity-score-matched for baseline characteristics. Main endpoints were progression-free survival (PFS), overall survival (OS), and relative survival (RS). The use of R-miniCHOP in DLBCL increased from 2% in 2014 to 15% in 2020. In total, 384 patients treated with R-miniCHOP and 384 patients treated with R-CHOP were included for comparison (median age; 81 years, stage 3-4; 68%). The median number of R-(mini)CHOP cycles was 6 (range, 1-8). The 2-year PFS, OS and RS were inferior for patients treated with R-miniCHOP compared to R-CHOP (PFS 51% vs. 68%, p < .01; OS 60% vs. 75%, p < .01; RS 69% vs. 86%, p < .01). In multivariable analysis, patients treated with R-miniCHOP had higher risk of all-cause mortality compared to patients treated with R-CHOP (HR 1.73; 95%CI, 1.39-2.17). R-miniCHOP is effective for most elderly patients. Although survival is inferior compared to R-CHOP, the use of R-miniCHOP as initial treatment is increasing. Therefore, fitness needs to be carefully weighed in treatment selection.

12-Year clinical and radiological results of a double-blind randomized controlled trial comparing posterior cruciate-retaining versus posterior-stabilized total knee arthroplasty.

BACKGROUND: A subject of ongoing debate among orthopedic surgeons is the importance of preserving the posterior cruciate ligament in total knee arthroplasty (TKA), but long-term survival studies are scarce. The aim of this study was to compare long-term survival rates, and clinical and radiological follow up of a double-blind randomized controlled trial comparing posterior cruciate-retaining (PCR) versus posterior-stabilizing (PS) implant design of an AGC TKA. METHODS: A total of 114 patients were included in the survival analysis (PCR n = 61; PS n = 53). Forty-five patients (PCR n = 25; PS n = 20) participated in the long-term follow up using patient-reported outcome measures (Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Short-Form Health Survey (SF-36) and Kujala score (measuring anterior knee pain)). Thirty-one patients were assessed with a physical test (Knee Society Score (KSS)) and radiographs. RESULTS: Overall survival rate was 95.6% (PCR 98.4% vs. PS 92.5%), with five patients having a major revision (PCR n = 1 vs. PS n = 4, respectively). Satisfying outcome scores for both groups were described at on average 12-year follow up with no significant differences in KSS knee and function scores, WOMAC, SF-36, or Kujala scores between groups. Radiographically, there were no findings of femoral or tibial loosening or polyethylene wear in either group. CONCLUSIONS: Good long-term survival rates were described for the PCR and the PS design of an AGC TKA. There were no significant differences in clinical and radiological outcomes between a PCR and a PS design 12 years postoperatively.

The relative and interactive impact of multiple risk factors in schizophrenia spectrum disorders: a combined register-based and clinical twin study.

BACKGROUND: Research has yielded evidence for genetic and environmental factors influencing the risk of schizophrenia. Numerous environmental factors have been identified; however, the individual effects are small. The additive and interactive effects of multiple risk factors are not well elucidated. Twin pairs discordant for schizophrenia offer a unique opportunity to identify factors that differ between patients and unaffected co-twins, who are perfectly matched for age, sex and genetic background. METHODS: Register data were combined with clinical data for 216 twins including monozygotic (MZ) and dizygotic (DZ) proband pairs (one or both twins having a schizophrenia spectrum diagnosis) and MZ/DZ healthy control (HC) pairs. Logistic regression models were applied to predict (1) illness vulnerability (being a proband v. HC pair) and (2) illness status (being the patient v. unaffected co-twin). Risk factors included: A polygenic risk score (PRS) for schizophrenia, birth complications, birth weight, Apgar scores, paternal age, maternal smoking, season of birth, parental socioeconomic status, urbanicity, childhood trauma, estimated premorbid intelligence and cannabis. RESULTS: The PRS [odds ratio (OR) 1.6 (1.1-2.3)], childhood trauma [OR 4.5 (2.3-8.8)], and regular cannabis use [OR 8.3 (2.1-32.7)] independently predicted illness vulnerability as did an interaction between childhood trauma and cannabis use [OR 0.17 (0.03-0.9)]. Only regular cannabis use predicted having a schizophrenia spectrum diagnosis between patients and unaffected co-twins [OR 3.3 (1.1-10.4)]. CONCLUSION: The findings suggest that several risk factors contribute to increasing schizophrenia spectrum vulnerability. Moreover, cannabis, a potentially completely avoidable environmental risk factor, seems to play a substantial role in schizophrenia pathology.

MRI signal intensity of anterior cruciate ligament graft after transtibial versus anteromedial portal technique (TRANSIG): A randomised controlled clinical trial.

BACKGROUND: Two primary surgical femoral drilling techniques are used to reconstruct the anterior cruciate ligament (ACL): the transtibial (TT) technique and the anteromedial portal (AMP) technique. Currently there is no consensus on which surgical technique elicits the best clinical and functional outcomes. MRI-derived measures of the signal intensity (SI) of the ACL graft have been described as an independent predictor of graft properties. The purpose of this study was to assess MRI-derived SI measurements of the ACL graft one year after ACL reconstruction, in order to compare graft maturation of both AMP and TT ACL reconstruction techniques. METHODS: This randomised controlled trial included 33 patients admitted for primary unilateral ACL reconstruction. Primary outcome was MRI Signal intensity ratio (SIR) of the ACL graft one year after ACL reconstruction. Differences in MRI SIR were assessed on two MRI sequencies: sagittal Proton Density Turbo Spin Echo weighted images (PDTSE) and 3D T2 Gradient Echo (T2*) weighted images. Analysis of interobserver and intraobserver variability was conducted for the SIR measurements. RESULTS: No difference in signal intensity of the graft was found between the TT and AMP techniques one year after ACL reconstruction (PDTSE p = 0.665, T2* p = 0.957). Both interobserver and intraobserver variability showed strong agreement (ICC 0.64-0.94). CONCLUSION: No differences in signal intensity of the graft on MRI were seen between the femoral drilling techniques one year after ACL reconstruction, suggesting similar graft maturation at that time. Follow-up studies are needed to determine whether graft intensity changes in the long term. LEVEL OF EVIDENCE: Therapeutic study with level of evidence I.

The role of computer-assisted cryotherapy in the postoperative treatment after total knee arthroplasty: positive effects on pain and opioid consumption.

PURPOSE: The aim of this study was to investigate whether computer-assisted cryotherapy is effective in reducing postoperative pain and analgesics consumption, next to improving functional outcome and patient satisfaction after total knee arthroplasty (TKA). The hypothesis is that computer-assisted cryotherapy has positive effects on postoperative pain after TKA. METHODS: A single-centre non-blinded randomised controlled trial was designed to study the early (first postoperative week) and late (2 and 6 weeks postoperatively) additive effect of computer-assisted cooling after TKA. Participants scheduled for a TKA were randomly allocated to a cold (cryotherapy) C-group or a regular (control) R-group. Next to usual postoperative care for both groups, the C-group received computer-assisted cryotherapy during the first seven postoperative days. Primary outcome was pain, monitored with the numerical rating scale for pain and use of opioid escape medication. Secondary outcomes were function and swelling, monitored by active range of motion, timed up and go test and circumference measurements; patient-reported outcome measurements (KOOS and WORQ questionnaires); and patient satisfaction, monitored by the numerical rating scale for satisfaction. RESULTS: 102 patients participated in this study, both groups contained 51 patients. On most days during the first week, patients in the C-group scored significantly lower NRS pain scores and registered significantly less use of opioid escape medication. In a sub-analysis of 57 patients using the same standard pain protocol, patients in the C-group (n = 28) used less oxycodone during the first postoperative week. There were no significant differences between both groups in active range of motion, timed up and go, or circumference measurements. For the WORQ questionnaire, there was a significant difference between the two groups 6 weeks postoperatively in favour of the C-group. This could be however due to a reduced validity of this questionnaire shortly after TKA. The satisfaction score was not significantly different between both groups. CONCLUSION: Computer-assisted cryotherapy following TKA can be beneficial during the first postoperative week in terms of pain reduction and diminished opioid consumption. No clear differences in knee function or swelling were seen. LEVEL OF EVIDENCE: Therapeutic study with level of evidence I.

The importance of continuous remnant preservation in anterior cruciate ligament reconstruction.

PURPOSE: Selective anteromedial or posterolateral bundle reconstruction is recognized as a treatment modality in partial anterior cruciate ligament (ACL) reconstruction (ACLR) with a biomechanically sufficient ACL remnant. However, there is paucity in literature investigating clinical outcomes of standard ACLR with preservation of residual continuous but biomechanically insufficient ACL tissue. The aim of this study was to investigate the influence of preservation of residual continuous but biomechanical insufficient ACL tissue in standard ACLR on complication and repeat surgery rate, and patient reported and clinical outcome. METHODS: The retrospective cohort comprised 134 patients (age 23 ± 7 years; Tegner 6 ± 3) with an isolated acute ACL tear. In 67 patients, residual continuous but biomechanically insufficient ACL tissue was present and preserved based on visual inspection, probing of the ACL tissue and Lachman test under arthroscopic view (standard reconstruction with tissue preservation; SRTP). These patients were matched to 67 patients that underwent ACLR where no residual ACL tissue could be preserved (standard reconstruction; SR) based on gender, age and chondral and/or meniscal status. Clinical failure (recurrent instability, pathological ACL graft laxity and/or ACL graft discontinuity), other complication and repeat-surgery rate within index surgery and 1-year and within index surgery and 2-year follow-up, and patient reported and clinical outcomes at 1-year and at 2-year follow-up were compared. RESULTS: A statistically significant lower clinical failure rate within index surgery and 1-year (SRTP, 3%; SR, 13%; P = 0.028) and within index surgery and 2-year follow-up (SRTP, 3%; SR, 23%; P = 0.001), and revision ACL surgery rate within index surgery and 1-year (SRTP, 2%; ST, 10%; P = 0.029) and within index surgery and 2-year follow-up (SRTP, 2%; SR, 18%; P = 0.001) was found in the SRTP group. No statistically significant differences were found for other investigated outcomes in patients that were without clinical failure. CONCLUSION: This study shows that in ACLR surgery, preservation of residual continuous but biomechanical insufficient ACL tissue might lead to lower clinical failure rate and ACL revision surgery rate within index surgery and 1-year, and within index surgery and 2-year follow-up compared to standard ACLR where no residual continuous ACL tissue could be preserved. LEVEL OF EVIDENCE: III.

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST).

BACKGROUND: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. AIMS: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. METHODS: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. BASELINE RESULTS: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. CONCLUSION: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Anterolateral proximal tibial opening wedge osteotomy for biplanar correction in genu valgum recurvatum using patient specific instrumentation (PSI). A technical note.

BACKGROUND: Biplanar anterolateral proximal tibial opening wedge osteotomy has been described as successful for patients with combined recurvatum and valgus alignment. As it is a correction in two planes, it is a technically demanding procedure. We report the use of a novel technique with patient specific instrumentation (PSI) guides for different steps, aiming to reduce the complexity of this procedure. METHODS: One patient was treated for genu valgum recurvatum. A virtual surgical plan was made. A two-step PSI approach was used, consisting of an osteotomy guide and a repositioning guide and a custom trial wedges. RESULTS: Follow-up showed full function and improved VAS and KOOS scores. A neutral alignment was achieved. There was 2.76 degrees less varus compared to pre-operative planning, 1.24 degrees of excess slope and a rotational difference of 0.10 degrees. Saw plane accuracy was within 1 mm. CONCLUSIONS: PSI is a recent technical addition to HTOs as a modality to improve accuracy and reduce surgical complexity. Pre-planning and PSI use in an anterolateral opening wedge PTO allowed for an accurate and reproducible biplanar correction in genu valgum recurvatum. Accuracy was comparable to PSI use in lateral open wedge high tibial osteotomies.

Recovery Courses of Patients Who Return to Work by 3, 6 or 12 Months After Total Knee Arthroplasty.

Purpose This study compared the preoperative levels and postoperative recovery courses of physical and mental impairments, activity limitations and participation restrictions of working-age patients who return to work (RTW) by 3, 6 or 12 months after total knee arthroplasty (TKA). Methods A prospective survey study including TKA patients (aged < 65) (n = 146) who returned to work (RdTW) in the first postoperative year. Three groups were compared: those who returned by 3 (n = 35), 6 (n = 40) or 12 (n = 29) months. Surveys were completed preoperatively and at 6 weeks and 3, 6 and 12 months postoperatively. Outcomes represented domains of the International Classification of Functioning, i.e. physical impairments (pain, stiffness, vitality), mental impairments (mental health and depressive symptoms), activity limitations (physical functioning) and participation restrictions (social and work functioning). Results Preoperative knee-specific pain and physical functioning levels were better among patients who RdTW by 3 months, compared to those who returned by 12 months. Patients who RdTW by 3 months experienced significantly better recovery from physical impairments than those who returned by 6 months (on general pain) or 12 months (on general and knee-specific pain and on stiffness). Patients returning by 3 months experienced significantly better recovery from activity limitations (on knee-specific physical functioning). Conclusions To optimize return to work outcome after TKA surgery, the focus should lie on physical impairments (general and knee-specific pain, stiffness) and activity limitations (knee-specific physical functioning) during recovery.

Genetic and environmental influences on circulating NK and T cells and their relation to bipolar disorder.

BACKGROUND: In previous studies we found mild deficiencies of circulating T cells in patients with bipolar disorder (BD) and children at risk for BD, correlating to a higher inflammatory state. The genetic and environmental influences on these T cell deficiencies in association with BD development are unknown. OBJECTIVES: The aim is to quantify genetic and environmental factors that contribute to the association between the liability to develop BD and T cell deficiencies. METHODS: Participants of a Dutch bipolar twin study (11 monozygotic BD twin pairs, 15 dizygotic BD twin pairs, 15 monozygotic and 12 dizygotic healthy twin pairs) were included. A detailed FACS analysis of frozen stored leukocytes was carried out to determine the percentages of T cells and various other leukocyte and lymphocyte subsets. A bivariate liability threshold twin model was used to determine genetic and environmental (common and unique) influences on the correlation between BD and the various subsets. RESULTS: Lower percentages of T cells and higher percentages of NK cells were associated with the familial liability to develop BD. Neither genetic nor shared or unique environmental factors could explain the associations. Lithium usage explained part of the association for T cells, smoking in part that for NK cells. CONCLUSIONS: Our results confirm that BD is the result of a complex interaction between various genetic and environmental risk factors, in which T and NK cells act as important intermediate immune players.

Auditory hallucinations in adults with hearing impairment: a large prevalence study.

BACKGROUND: Similar to visual hallucinations in visually impaired patients, auditory hallucinations are often suggested to occur in adults with hearing impairment. However, research on this association is limited. This observational, cross-sectional study tested whether auditory hallucinations are associated with hearing impairment, by assessing their prevalence in an adult population with various degrees of objectified hearing impairment. METHODS: Hallucination presence was determined in 1007 subjects aged 18-92, who were referred for audiometric testing to the Department of ENT-Audiology, University Medical Center Utrecht, the Netherlands. The presence and severity of hearing impairment were calculated using mean air conduction thresholds from the most recent pure tone audiometry. RESULTS: Out of 829 participants with hearing impairment, 16.2% (n = 134) had experienced auditory hallucinations in the past 4 weeks; significantly more than the non-impaired group [5.8%; n = 10/173; p < 0.001, odds ratio 3.2 (95% confidence interval 1.6-6.2)]. Prevalence of auditory hallucinations significantly increased with categorized severity of impairment, with rates up to 24% in the most profoundly impaired group (p < 0.001). The corrected odds of hallucination presence increased 1.02 times for each dB of impairment in the best ear. Auditory hallucinations mostly consisted of voices (51%), music (36%), and doorbells or telephones (24%). CONCLUSIONS: Our findings reveal that auditory hallucinations are common among patients with hearing impairment, and increase with impairment severity. Although more research on potential confounding factors is necessary, clinicians should be aware of this phenomenon, by inquiring after hallucinations in hearing-impaired patients and, conversely, assessing hearing impairment in patients with auditory hallucinations, since it may be a treatable factor.

Modelling farmer choices for water security measures in the Litani river basin in Lebanon.

Lebanon is facing an increasing water supply deficit due to the increasing demand for freshwater, decreasing surface and groundwater resources and malfunctioning water governance structures. Technological and policy changes are needed to alleviate the impact of water scarcity and secure water in the future. This paper investigates farmers' preferences and willingness to pay (WTP) in a choice experiment for a series of water saving measures at plot and irrigation district level, including more timely information of water delivery. These measures are expected to strengthen water security and use water more efficiently. Farmers are willing to pay higher water prices of $0.32/m3 and $0.22/m3 to support the implementation of water saving measures at plot level and the installation of water metering devices across the irrigation district, respectively. They are not willing to pay extra for obtaining information related to their water delivery earlier in time if this means that they will also have to pay earlier in the year for the water. Farmers with higher income and education levels who decide on their cropping pattern based on expected rainfall data are more interested in taking action than farmers whose cropping decisions are primarily based on last year's sales prices. The study shows that when aiming to design more effective sustainable water management strategies, accounting for farmers' needs and preferences, their age also has to be considered: younger farmers (<40 years) are on average more interested in and willing to pay more for new water saving measures than older farmers (>40 years).

Elastic compression stockings one year after DVT diagnosis: Who might discontinue?

BACKGROUND: Elastic compression stockings (ECS) are uncomfortable to wear but may prevent post-thrombotic syndrome (PTS). The ability to predict PTS may help clinical decision making regarding the optimal duration of ECS after deep vein thrombosis (DVT). AIMS: Predefined endpoint analysis of the Octavia study that randomized patients who compliantly used ECS up to one year after DVT to continue or discontinue ECS treatment. Primary aim was to identify predictors of PTS. METHODS: Patient characteristics were collected and ultrasonography was performed to assess reflux, residual thrombosis and persistent thrombus load 12 months after DVT. Multivariable analyses were performed to identify factors related to PTS. RESULTS: Thrombus score ≥ 3, BMI ≥ 26, duration of symptoms before DVT diagnosis ≥ 8 days and a Villalta score of 2-4 points were statistically significant predictors of PTS. The predictive value for PTS for the assessed variables was not different between the 2 treatment groups. In the stop ECS group, 3.2% (95%CI 0.08-18) of patients without any predictors for PTS were diagnosed with mild PTS during follow-up, and none with severe PTS, for a sensitivity of 98% (95% CI 89-100), a specificity of 14% (95% CI 10-20), a positive predictive value of 20% (95% CI 19-22), and a negative predictive value of 97% (95% CI 81-100). CONCLUSION: We identified 4 predictors of PTS occurring in the 2nd year after DVT. Our findings may be used to decide on whether to continue ECS treatment for an additional year, after one year of compliant ECS use, keeping in mind that patients with none of the predictors will have the lowest PTS incidence.

Peptidyl-Prolyl-cis/trans-Isomerases Mip and PpiB of Legionella pneumophila Contribute to Surface Translocation, Growth at Suboptimal Temperature, and Infection.

The gammaproteobacterium Legionella pneumophila is the causative agent of Legionnaires' disease, an atypical pneumonia that manifests itself with severe lung damage. L. pneumophila, a common inhabitant of freshwater environments, replicates in free-living amoebae and persists in biofilms in natural and man-made water systems. Its environmental versatility is reflected in its ability to survive and grow within a broad temperature range as well as its capability to colonize and infect a wide range of hosts, including protozoa and humans. Peptidyl-prolyl-cis/trans-isomerases (PPIases) are multifunctional proteins that are mainly involved in protein folding and secretion in bacteria. In L. pneumophila the surface-associated PPIase Mip was shown to facilitate the establishment of the intracellular infection cycle in its early stages. The cytoplasmic PpiB was shown to promote cold tolerance. Here, we set out to analyze the interrelationship of these two relevant PPIases in the context of environmental fitness and infection. We demonstrate that the PPIases Mip and PpiB are important for surfactant-dependent sliding motility and adaptation to suboptimal temperatures, features that contribute to the environmental fitness of L. pneumophila Furthermore, they contribute to infection of the natural host Acanthamoeba castellanii as well as human macrophages and human explanted lung tissue. These effects were additive in the case of sliding motility or synergistic in the case of temperature tolerance and infection, as assessed by the behavior of the double mutant. Accordingly, we propose that Mip and PpiB are virulence modulators of L. pneumophila with compensatory action and pleiotropic effects.

Progression of ductal carcinoma in situ to invasive breast cancer: comparative genomic sequencing.

Several models have been described as potential mechanisms for the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC). The aim of our study was to increase our understanding of DCIS progression by using massive parallel sequencing of synchronous DCIS and IBC. We included patients with synchronous DCIS and IBC (n = 4). Initially, IBC and normal tissue were subjected to whole exome sequencing. Subsequently, targeted sequencing was performed to validate those tumor-specific variants identified by whole exome sequencing. Finally, we analyzed whether those specific variants of the invasive component were also present in the DCIS component. There was a high genomic concordance between synchronous DCIS and IBC (52 out of 92 mutations were present in both components). However, the remaining mutations (40 out of 92) were restricted to the invasive component. The proportion of tumor cells with these mutations was higher in the invasive component compared to the DCIS component in a subset of patients. Our findings support the theory that the progression from DCIS to IBC could be driven by the selection of subclones with specific genetic aberrations. This knowledge improves our understanding of DCIS progression, which may lead to the identification of potential markers of progression and novel therapeutic targets in order to develop a more personalized treatment of patients with DCIS.

Publisher Correction: Associations between subjective well-being and subcortical brain volumes.

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