Three and twelve-month analysis of the PROM-Q study: comparison of patient-reported outcome measures using the BREAST-Q questionnaire in pre- vs. sub-pectoral implant-based immediate breast reconstruction.

PURPOSE: Implant-based breast reconstruction (IBR) is being increasingly performed with implant placed above the pectoral muscle (pre-pectoral), instead of below the pectoral muscle (sub-pectoral). Currently, there is a lack of comparative data on clinical and patient-perceived outcomes between pre- vs. sub-pectoral IBR. We investigated whether this difference in surgical approach influenced clinical or patient-perceived outcomes. METHODS: This prospective non-randomised longitudinal cohort study (ClinicalTrials.gov identifier: NCT04842240) recruited patients undergoing immediate IBR at the Leeds Breast Unit (Sep 2019-Sep 2021). Data collection included patient characteristics and post-operative complications. Patient-Reported Outcome Measures were collected using the BREAST-Q questionnaire at baseline, 2 weeks, 3- and 12-months post-surgery. RESULTS: Seventy-eight patients underwent IBR (46 patients pre-pectoral; 59% vs. 32 patients sub-pectoral; 41%). Similar complication rates were observed (15.2% pre-pectoral vs. 9.4% sub-pectoral; p = 0.44). Overall implant loss rate was 3.8% (6.5% pre-pectoral vs. 0% sub-pectoral; p = 0.13). Respective median Breast-Q scores for pre- and sub-pectoral IBR at 3 months were: breast satisfaction (58 vs. 48; p = 0.01), psychosocial well-being (60 vs. 57; p = 0.9), physical well-being (68 vs. 76; p = 0.53), and Animation Q scores (73 vs. 76; p = 0.45). Respective Breast-Q scores at 12 months were: breast satisfaction (58 vs. 53; p = 0.3), psychosocial well-being (59 vs. 60; p = 0.9), physical well-being (68 vs. 78; p = 0.18), and Animation Q scores (69 vs. 73; p = 0.4). CONCLUSIONS: This study demonstrates equivalent clinical and patient-perceived outcomes between pre- and sub-pectoral IBR. The study findings can be utilised to aid informed decision making regarding either surgical option.

Floral freezing tolerance is tied to flowering time in North American woody plant species.

BACKGROUND AND AIMS: As winter and spring temperatures continue to increase, the timing of flowering and leaf out is advancing in many seasonally cold regions. This advancement could put plants that flower early in the spring at risk of decreased reproduction in years when there are late freeze events. Unfortunately, relatively little is known about floral freezing tolerance in forest communities. In this study, we examined the impact of freezing temperatures on the flowers of woody plants in a region where there is rapid winter warming in North America. METHODS: We subjected the flowers of twenty-five woody species to a hard (-5ºC) and a light freeze (0ºC). We assessed tissue damage using electrolyte leakage. In a subset of species, we also examined the impact of a hard freeze on pollen tube growth. To determine if the vulnerability of flowers to freezing damage relates to flowering time and to examine the responsiveness of flowering time to spring temperature, we recorded the date of first flower for our study species for three years. KEY RESULTS AND CONCLUSIONS: Across species, we found that floral freezing tolerance was strongly tied to flowering time with the highest freezing tolerance occurring in plants that bloomed earlier in the year. We hypothesize that these early blooming species are unlikely to be impacted by a false spring. Instead, the most vulnerable species to a false spring should be those that bloom later in the season. The flowering time in these species is also more sensitive to temperature, putting them at a great risk of experiencing a false spring. Ultimately, floral damage in one year will not have a large impact on species fitness, but if false springs become more frequent, there could be long-term impacts on reproduction of vulnerable species.

Injection Site Reactions with Long-Term Pegcetacoplan Use in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Brief Report.

INTRODUCTION: Pegcetacoplan is a targeted complement component 3 (C3) therapy approved for adults with paroxysmal nocturnal hemoglobinuria (PNH; US) or PNH plus anemia despite C5-targeted therapy for ≥ 3 months (EU). Patients with PNH receiving pegcetacoplan in the phase 3 PEGASUS trial who experienced injection site reactions (ISRs) mostly experienced mild events. We evaluated ISR incidence and severity with longer-term treatment in the PEGASUS cohort of the Study 307 open-label extension (307 OLE). METHODS: Patients from PEGASUS enrolled in the 307 OLE continued pegcetacoplan subcutaneous self-administration twice or three times weekly or every 3 days for an additional 48 weeks. ISRs were coded as adverse events (AEs) or treatment-emergent AEs (TEAEs) and summarized by MedDRA System Organ Class and Preferred Term. RESULTS: As of August 27, 2021, 58/64 patients from PEGASUS completed an additional 48 weeks of treatment in the 307 OLE (median treatment duration 337.0 [range 55-344] days); 95.3% (61/64) of patients achieved compliance ≥ 80%. ISRs occurred in 9/64 (14.1%) patients in the 307 OLE, which was lower than observed at PEGASUS completion (20/77; 26.0%). Most patients with ISRs in the 307 OLE had events with a maximum severity of mild (7/9 patients; 77.8%). Injection site erythema and induration were the most common overall (4/64 patients each; 6.3%) and pegcetacoplan-related (3/64 patients each; 4.7%) ISRs. The exposure-adjusted rates of these events were each 6.5 per 100 patient-years. No ISRs were classified as severe or serious TEAEs or led to drug discontinuation. CONCLUSION: Though ISRs were common, most were mild, and the percentage of patients reporting ISRs declined from PEGASUS through the 307 OLE. Patient compliance remained high, and no patients discontinued because of ISRs, suggesting that ISRs do not pose a barrier to long-term pegcetacoplan treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT03500549 (PEGASUS) and NCT03531255 (307 OLE).

A UK consensus statement on thromboprophylaxis for autologous breast reconstruction.

Microsurgical breast reconstruction accounts for 22% of breast reconstructions in the UK. Despite thromboprophylaxis, venous thromboembolism (VTE) occurs in up to 4% of cases. Using a Delphi process, this study established a UK consensus on VTE prophylaxis strategy, for patients undergoing autologous breast reconstruction using free-tissue transfer. It captured geographically divergent views, producing a guide that reflected the peer opinion and current evidence base. METHODS: Consensus was ascertained using a structured Delphi process. A specialist from each of the UK's 12 regions was invited to the expert panel. Commitment to three to four rounds of questions was sought at enrollment. Surveys were distributed electronically. An initial qualitative free-text survey was distributed to identify likely lines of consensus and dissensus. Each panelist was provided with full-text versions of key papers on the topic. Initial free-text responses were analyzed to develop a set of structured quantitative statements, which were refined via a second survey as a consensus was approached. RESULTS: The panel comprised 18 specialists: plastic surgeons and thrombosis experts from across the UK. Each specialist completed three rounds of surveys. Together, these plastic surgeons reported having performed more than 570 microsurgical breast reconstructions in the UK in 2019. A consensus was reached on 27 statements, detailing the assessment and delivery of VTE prophylaxis. CONCLUSION: To our knowledge, this is the first study to collate current practice, expert opinion from across the UK, and a literature review. The output was a practical guide for VTE prophylaxis for microsurgical breast reconstruction in any UK microsurgical breast reconstruction unit.

Pegcetacoplan controls hemolysis in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis. Pegcetacoplan is the first C3-targeted therapy approved for adults with PNH (United States), adults with PNH with inadequate response or intolerance to a C5 inhibitor (Australia), and adults with anemia despite C5-targeted therapy for ≥3 months (European Union). PRINCE was a phase 3, randomized, multicenter, open-label, controlled study to evaluate the efficacy and safety of pegcetacoplan vs control (supportive care only; eg, blood transfusions, corticosteroids, and supplements) in complement inhibitor-naive patients with PNH. Eligible adults receiving supportive care only for PNH were randomly assigned and stratified based on their number of transfusions (<4 or ≥4) 12 months before screening. Patients received pegcetacoplan 1080 mg subcutaneously twice weekly or continued supportive care (control) for 26 weeks. Coprimary end points were hemoglobin stabilization (avoidance of >1-g/dL decrease in hemoglobin levels without transfusions) from baseline through week 26 and lactate dehydrogenase (LDH) change at week 26. Overall, 53 patients received pegcetacoplan (n = 35) or control (n = 18). Pegcetacoplan was superior to control for hemoglobin stabilization (pegcetacoplan, 85.7%; control, 0; difference, 73.1%; 95% confidence interval [CI], 57.2-89.0; P < .0001) and change from baseline in LDH (least square mean change: pegcetacoplan, -1870.5 U/L; control, -400.1 U/L; difference, -1470.4 U/L; 95% CI, -2113.4 to -827.3; P < .0001). Pegcetacoplan was well tolerated. No pegcetacoplan-related adverse events were serious, and no new safety signals were observed. Pegcetacoplan rapidly and significantly stabilized hemoglobin and reduced LDH in complement inhibitor-naive patients and had a favorable safety profile. This trial was registered at www.clinicaltrials.gov as NCT04085601.

Hyponatremia after Autologous Breast Reconstruction: A Cohort Study Comparing Two Fluid Management Protocols.

BACKGROUND: Perioperative fluid management is an important component of enhanced recovery pathways for microsurgical breast reconstruction. Historically, fluid management has been liberal. Little attention has been paid to the biochemical effects of different protocols. This study aims to reduce the risk of postoperative hyponatremia by introducing a new fluid management protocol. METHODS: A single-institution cohort study comparing a prospective series of patients was managed using a new "modestly restrictive" fluid postoperative fluid management protocol to a control group managed with a "liberal" fluid management protocol. RESULTS: One-hundred thirty patients undergoing microsurgical breast reconstruction, at a single institution during 2021, are reported. Hyponatremia is demonstrated to be a significant risk with the original liberal fluid management protocol. At the end of the first postoperative day, mean fluid balance was +2,838 mL (± 1,630 mL). Twenty-four patients of sixty-five (36%) patients had low blood sodium level, 14% classified as moderate-to-severe hyponatremia. Introducing a new, "modestly-restrictive" protocol reduced mean fluid balance on day 1 to +844 mL (±700) (p ≤ 0.0001). Incidence of hyponatremia reduced from 36 to 14% (p = 0.0005). No episodes of moderate or severe hyponatremia were detected. Fluid intake, predominantly oral water, between 8am and 8pm on the first postoperative day is identified as the main risk factor for developing hyponatremia (odds ratio [OR]: 7; p = 0.019). Modest fluid restriction, as guided by the new protocol, protects patients from low sodium level (OR: 0.25; confidence interval: 95%; 0.11-1.61; p = 0.0014). CONCLUSION: The original "liberal" fluid management protocol encouraged unrestricted postoperative oral intake of water. Patients were often advised to consume in excess of 5 L in the first 24 hours. This unintentionally, but frequently, was associated with moderate-to-severe hyponatremia. We present a new protocol characterized by early cessation of intravenous fluid and an oral fluid limit of 2,100 mL/day associated with a significant reduction in the incidence of hyponatremia and fluid overload.

Leaf out time correlates with wood anatomy across large geographic scales and within local communities.

There is a long-standing idea that the timing of leaf production in seasonally cold climates is linked to xylem anatomy, specifically vessel diameter because of the hydraulic requirements of expanding leaves. We tested for a relationship between the timing of leaf out and vessel diameter in 220 plants in three common gardens accounting for species' phylogenetic relationships. We investigated how vessel diameter related to wood porosity, plant height and leaf length. We also used dye perfusion tests to determine whether plants relied on xylem produced during the previous growing season at the time of leaf out. In all three gardens, there was later leaf out in species with wider vessels. Ring-porous species had the widest vessels, exhibited latest leaf out and relied less on xylem made during the previous growing season than diffuse-porous species. Wood anatomy and leaf phenology did not exhibit a phylogenetic signal. The timing of leaf out is correlated with wood anatomy across species regardless of species' geographic origin and phylogenetic relationships. This correlation could be a result of developmental and physiological links between leaves and wood or tied to a larger safety efficiency trade-off.

Early spring flowers rely on xylem hydration but are not limited by stem xylem conductivity.

Many woody plants produce large floral displays early in the spring when xylem transport can be variable and often reduced. To determine whether stem hydraulics impact floral water use, we quantified floral transpiration and tested whether it was correlated with stem xylem conductivity in five temperate woody species that flower before producing leaves. We measured inflorescence gas exchange, examined the relationship between diffusive conductance and inflorescence morphology, and estimated the amount of water supplied to an inflorescence by the phloem. We also tested for correlation between transpiration and native stem xylem conductivity for branches with leaves and branches with flowers. The flowers of our study species obtain most of their water from the xylem. Diffusive conductance was higher in small inflorescences, but water content and daily transpiration rates were greater for larger inflorescences. We found no correlation between floral transpiration per branch and stem xylem conductivity within species. The data suggest that inflorescence water loss during anthesis is not limited by the xylem in our study species. We highlight the impact of floral morphology on hydraulic traits and encourage exploration into temporal shifts in floral hydration.

Seasonal changes in temperate woody plant phloem anatomy and physiology: implications for long-distance transport.

Seasonal changes in climate are accompanied by shifts in carbon allocation and phenological changes in woody angiosperms, the timing of which can have broad implications for species distributions, interactions and ecosystem processes. During critical transitions from autumn to winter and winter to spring, physiological and anatomical changes within the phloem could impose a physical limit on the ability of woody angiosperms to transport carbon and signals. There is a paucity of the literature that addresses tree (floral or foliar) phenology, seasonal phloem anatomy and seasonal phloem physiology together, so our knowledge of how carbon transport could fluctuate seasonally, especially in temperate climates is limited. We review phloem phenology focussing on how sieve element anatomy and phloem sap flow could affect carbon availability throughout the year with a focus on winter. To investigate whether flow is possible in the winter, we construct a simple model of phloem sap flow and investigate how changes to the sap concentration, pressure gradient and sieve plate pores could influence flow during the winter. Our model suggests that phloem transport in some species could occur year-round, even in winter, but current methods for measuring all the parameters surrounding phloem sap flow make it difficult to test this hypothesis. We highlight outstanding questions that remain about phloem functionality in the winter and emphasize the need for new methods to address gaps in our knowledge about phloem function.

Coordination of spring vascular and organ phenology in deciduous angiosperms growing in seasonally cold climates.

In seasonally cold climates, many woody plants tolerate chilling and freezing temperatures by ceasing growth, shedding leaves and entering dormancy. At the same time, transport within these plants often decreases as the vascular system exhibits reduced functionality. As spring growth requires water and nutrients, we ask the question: how much does bud, leaf and flower development depend on the vasculature in spring? In this review, we present what is known about leaf, flower and vascular phenology to sort out this question. In early stages of bud development, buds rely on internal resources and do not appear to require vascular support. The situation changes during organ expansion, after leaves and flowers reconnect to the stem vascular system. However, there are major gaps in our understanding of the timing of vascular development, especially regarding the phloem, as well as the synchronization among leaves, flowers, stem and root vasculature. We believe these gaps are mainly the outcome of research completed in silo and urge future work to take a more integrative approach. We highlight current challenges and propose future directions to make rapid progress on this important topic in upcoming years.

Ontogenetic scaling of phloem sieve tube anatomy and hydraulic resistance with tree height in Quercus rubra.

PREMISE: The dimensions of phloem sieve elements have been shown to vary as a function of tree height, decreasing hydraulic resistance as the transport pathway lengthens. However, little is known about ontogenetic patterns of sieve element scaling. Here we examine within a single species (Quercus rubra) how decreases in hydraulic resistance with distance from the plant apex are mediated by overall plant size. METHODS: We sampled and imaged phloem tissue at multiple heights along the main stem and in the live crown of four size classes of trees using fluorescence and scanning electron microscopy. Sieve element length and radius, the number of sieve areas per compound plate, pore number, and pore radius were used to calculate total hydraulic resistance at each sampling location. RESULTS: Sieve element length varied with tree size, while sieve element radius, sieve pore radius, and the number of sieve areas per compound plate varied with sampling position. When data from all size classes were aggregated, all four variables followed a power-law trend with distance from the top of the tree. The net effect of these ontogenetic scalings was to make total hydraulic sieve tube resistance independent of tree height from 0.5 to over 20 m. CONCLUSIONS: Sieve element development responded to two pieces of information, tree size and distance from the apex, in a manner that conserved total sieve tube resistance across size classes. A further differentiated response between the phloem in the live crown and in the main stem is also suggested.

Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele.

BACKGROUND: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes. METHODS: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV1) at week 4. RESULTS: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV1 that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

Clinical development of triple-combination CFTR modulators for cystic fibrosis patients with one or two F508del alleles.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator gene (CFTR) that result in diminished quantity and/or function of the CFTR anion channel. F508del-CFTR, the most common CF-causing mutation (found in ∼90% of patients), causes severe processing and trafficking defects, resulting in decreased CFTR quantity and function. CFTR modulators are medications that increase the amount of mature CFTR protein (correctors) or enhance channel function (potentiators) at the cell surface. Combinations of CFTR correctors and potentiators (i.e. lumacaftor/ivacaftor, tezacaftor/ivacaftor) have demonstrated clinical benefit in subsets of patients. However, none are approved for patients with CF heterozygous for F508del-CFTR and a minimal function mutation, i.e. a mutation that produces either no protein or protein that is unresponsive to currently approved CFTR modulators. Next-generation CFTR correctors VX-659 and VX-445, each in triple combination with tezacaftor and ivacaftor, improve CFTR processing, trafficking and function in vitro and have demonstrated clinical improvements in phase 2 studies in patients with CF with one or two F508del-CFTR alleles. Here, we present the rationale and design of four randomised phase 3 studies, and their open-label extensions, evaluating VX-659 (ECLIPSE) or VX-445 (AURORA) plus tezacaftor and ivacaftor in patients with one or two F508del-CFTR alleles.

Measuring Phloem Transport Velocity on a Tissue Level Using a Phloem-Mobile Dye.

Here we describe an in vivo dye-tracking method for measuring phloem transport velocity in seedlings, leaves and petioles and potentially other translucent plant tissues. The method requires measurement of the fluorescent signal of a phloem-mobile fluorescent dye using sensitive photo-sensors placed external to the plant. Following dye application, velocity is determined using laser fluorescence bleaching and measuring the time it takes for the bleach front to reach a light sensor. This method can be used to measure phloem transport velocity on intact plants with minimal disturbance and has a potential to be used under a variety of growth conditions and in the field. Because there are large differences among species in their anatomy, this method should be optimized to individual plants and tissue types.

A temporal shift in resource allocation facilitates flowering before leaf out and spring vessel maturation in precocious species.

PREMISE OF THE STUDY: New growth in the spring requires resource mobilization in the vascular system at a time when xylem and phloem function are often reduced in seasonally cold climates. As a result, the timing of leaf out and/or flowering could depend on when the vascular system resumes normal function in the spring. This study investigated whether flowering time is influenced by vascular phenology in plants that flower precociously before they have leaves. METHODS: Flower, leaf, and vascular phenology were monitored in pairs of precocious and non-precocious congeners. Differences in resource allocation were quantified by measuring bud dry mass and water content throughout the year, floral hydration was modelled, and a girdling treatment completed on branches in the field. KEY RESULTS: Precocious flowering species invested more in floral buds the year before flowering than did their non-precocious congeners, thus mobilizing less water in the spring, which allowed flowering before new vessel maturation. CONCLUSIONS: A shift in the timing of resource allocation in precocious flowering plants allowed them to flower before the production of mature vessels and minimized the significance of seasonal changes in vascular function to their flowering phenology. The low investment required to complete floral development in the spring when the plant vascular system is often compromised could explain why flowers can emerge before leaf out.

Pilot Intervention Addressing Social Support and Functioning of Low Socioeconomic Status Older Adults With ESRD: The Seniors Optimizing Community Integration to Advance Better Living with ESRD (SOCIABLE) Study.

RATIONALE & OBJECTIVE: Older adults with end-stage kidney disease have increased morbidity, fatigue, and decreased physical function, which can inhibit self-care and social engagement. We pilot tested a home-based program to improve physical and social functioning of low socioeconomic status older adults treated with hemodialysis (HD). STUDY DESIGN: Qualitative study and randomized waitlist control intervention. SETTING & PARTICIPANTS: Older adult HD patients in Baltimore, MD. INTERVENTIONS: We identified functional needs and home environmental barriers to social engagement through focus groups; mapped findings onto aspects of an established program, which includes home visits with an occupational therapist, nurse, and handyman to provide ≤$1,300 worth of repairs, modifications, and devices; and piloted the program (Seniors Optimizing Community Integration to Advance Better Living with ESRD [SOCIABLE]) among 12 older adult HD patients. We delivered the services over 5 months in a staggered fashion. OUTCOMES: Feasibility and acceptability of the intervention and change in disability scores. RESULTS: Focus group themes included fatigue, lack of social support, and desire to live independently. SOCIABLE pilot participants were recruited from 2 dialysis units and all were African American (50% men); mean age was 69 years. At baseline, the mean disability score for activities of daily living (ADLs) was 4.4 and for instrumental ADLs (IADLs) was 6.3 (both out of a possible 16). Among the 9 participants alive at follow-up, there was 100% intervention completion and outcomes assessment. All treated participants improved a mean score of 2.3 for ADL and 2.6 for IADL disability, and social support and social network scores improved by 4.8 and 4.6, respectively. LIMITATIONS: Small sample size; all participants were African American. CONCLUSIONS: A home-based intervention addressing physical and social functioning of low socioeconomic status older adults on HD therapy was feasible and acceptable.