Does the use of acellular dermal matrices (ADM) in women undergoing pre-pectoral implant-based breast reconstruction increase operative success versus non-use of ADM in the same setting? A systematic review protocol.

BACKGROUND: Breast cancer is the most common malignancy among women in the UK. Following mastectomy, reconstruction is now integral to the surgical management of breast cancer, of which implant-based reconstruction (IBBR) is the most common type. IBBR initially evolved from pre-pectoral to post-pectoral due to complications, but with developments in oncoplastic techniques and new implant technology, interest in pre-pectoral IBBR has increased. Many surgeons use acellular dermal matrices (ADM); however, there is little evidence in literature as to whether this improves surgical outcomes in terms of complications, failure and patient satisfaction. This review aims to assess the available evidence as to whether there is a difference in surgical outcomes for breast reconstructions using ADM versus non-use of ADM. METHODS: A database search will be performed using Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Clinicaltrials.org. The search timeframe will be 10 years. Studies will be screened using inclusion and exclusion criteria and data extracted into a standardised spreadsheet. Risk of bias will be assessed. Screening, extraction and risk-of-bias assessments will be performed independently by two reviewers and discrepancies discussed and rectified. Data analysis and meta-analysis will be performed using Microsoft Excel and R software. Forest plots will be used for two-arm studies to calculate heterogeneity and p-value for overall effect. DISCUSSION: With the renaissance of pre-pectoral IBBR, it is important that surgeons have adequate evidence available to assist operative decision-making. Assessing evidence in literature is important to help surgeons determine whether using ADM for IBBR is beneficial compared to non-use of ADM. This has potential impacts for patient complications, satisfaction and cost to healthcare trusts. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2023 CRD42023389072.

Fostering innovation and sustainable thinking in surgery: an evaluation of a surgical hackathon.

INTRODUCTION: Surgery represents a major source of carbon emissions, with numerous initiatives promoting more sustainable practices. Healthcare innovation and the development of a digitally capable workforce are fundamental in leveraging technologies to tackle challenges, including sustainability in surgery. METHODS: A surgical hackathon was organised with three major themes: (1) how to make surgery greener, (2) the future of plastic surgery in 10 years, and (3) improving healthcare outcomes using machine learning. Lectures were given on sustainability and innovation using the problem, innovation, market size, strategy and team (PIMST) framework to support their presentations, as well as technological support to translate ideas into simulations or minimum viable products. Pre- and post-event questionnaires were circulated to participants. RESULTS: Most attendees were medical students (65%), although doctors and engineers were also present. There was a significant increase in delegates' confidence in approaching innovation in surgery (+20%, p < 0.001). Reducing waste packaging (70%), promoting recyclable material usage (56%) and the social media dimension of public perceptions towards plastic surgery (40%) were reported as the most important issues arising from the hackathon. The top three prizes went to initiatives promoting an artificial intelligence-enhanced operative pathway, instrument sterilisation and an educational platform to teach students research and innovation skills. CONCLUSIONS: Surgical hackathons can result in significant improvements in confidence in approaching innovation, as well as raising awareness of important healthcare challenges. Future innovation events may build on this to continue to empower the future workforce to leverage technologies to tackle healthcare challenges such as sustainability.

UK esthetics associations: A robust safety net or credibility accessories?

BACKGROUND: Currently, safe practice in the UK esthetics industry is largely reliant on self-regulatory bodies. If these bodies do not maintain high standards of safety guidelines and properly accredit practitioners, patient safety may be at risk. To our knowledge, no studies have addressed cosmetic self-regulatory bodies and their websites on Google, the most commonly used information source. This study aimed to map self-regulatory bodies on Google and evaluate their roles in the current UK esthetics industry. METHOD: We conducted a systematic search of Google Search results using eight search terms. The first 100 search results were screened against our eligibility criteria. We searched each website of a self-regulatory body for their requirements to join registers, membership fees, and features listed on the UK government's criteria for an effective self-regulatory body. RESULTS: We identified 22 self-regulating bodies for the UK esthetics industry. Only 15% of registers required an in-person assessment of cosmetic skills to qualify for membership. Of the self-regulatory bodies, 65% did not set clear standards and guidelines for practice. No qualifications were required by 14% of surgical and 31% of non-surgical bodies. The mean membership fee was £331. CONCLUSION: This study uncovered important information about the self-regulation of the esthetics industry in the UK. A significant majority of self-regulatory bodies did not meet best practices, potentially putting patients at risk. We recommend further studies screening a higher number of pages in a Google Search to scope all other existing self-regulatory bodies, due to the creation of Google "filter bubbles."

WALANT: Perceptions, approaches, and contraindications in a tertiary hand surgery unit.

Wide awake local anesthetic no tourniquet (WALANT) is gaining popularity amongst hand surgeons. Digital adrenaline use has been shown to be safe in multiple studies and the misconception forbidding it is receding. Phentolamine has been shown to safely reverse the effects of adrenaline should the feared complication of digital ischemia occur. A survey was circulated to 40 specialist practitioners who regularly perform hand procedures at a major tertiary plastic and hand surgery unit. Knowledge and understanding of WALANT, onset and duration of adrenaline effects and reversal was assessed. Whilst the majority of respondents (80%) recognized digital adrenaline use as safe, only 65% were aware of the delay until adrenaline takes full effect. Similarly, only 25% of respondents were aware of the duration of effect of adrenaline. Half of respondents were aware that phentolamine is the established reversal agent for adrenaline with only 20% knowing the correct dose. Given the lack of clinician knowledge surrounding adrenaline and its reversal, we feel that to safely undertake WALANT surgery at our Unit a WALANT protocol must be implemented. Drawing on the successes in the airline industry, a variety of safety frameworks have been established to deliver targeted education for prevention and eventual management of predictable risks. We plan to develop a checklist style protocol targeting the knowledge gaps raised in the survey. This will educate and equip all practitioners working with adrenaline with the knowledge to safely manage complications should they occur. LEVEL OF EVIDENCE: Level 5 (UK Oxford Centre for Evidence based Medicine (CEBM) Levels of Evidence).

The current progress and critical analysis of three-dimensional scanning and three-dimensional printing applications in breast surgery.

BACKGROUND: Several attempts have been made to develop a tool capable of evaluating breast shape and volume to aid surgical planning and outcome assessment. More recently, newer technologies such as three-dimensional (3D) scanning and 3D printing have been applied in breast assessment. The aim of this study was to review the literature to assess the applicability of 3D scanning and 3D printing in breast surgery. METHODS: A literature search was carried on PubMed, Google Scholar and OVID from January 2000 to December 2019 using the keywords '3D', 'Three-dimensional', 'Three/four dimensions' and 'Breast'. RESULTS: A total of 6564 articles were identified initially; the abstracts of 1846 articles were scanned, and 81 articles met the inclusion criteria and were included in this review. Articles were reviewed and classified according to their aims, study subjects, the software and hardware used, main outcomes and major limitations. CONCLUSIONS: These technologies are fast and easy to use, however, high costs, long processing times and the need for training might limit their application. To incorporate these technologies into standard healthcare, their efficacy and effectiveness must be demonstrated through multiple and rigorous clinical trials.

Safety of major reconstructive surgery during the peak of the COVID-19 pandemic in the United Kingdom and Ireland - multicentre national cohort study.

BACKGROUND: The safety of surgery during and after the coronavirus disease-2019 (COVID-19) pandemic is paramount. Early reports of excessive perioperative mortality in COVID-positive patients promoted the widespread avoidance of operations. However, cancelling or delaying operations for cancer, trauma, or functional restitution has resulted in increased morbidity and mortality. METHODS: A national multicentre cohort study of all major reconstructive operations carried out over a 12-week period of the 'COVID-19 surge' in the United Kingdom and Ireland was performed. Primary outcome was 30-day mortality and secondary outcome measures were major complications (Clavien-Dindo grade ≥3) and COVID-19 status of patients and healthcare professionals before and after surgery. RESULTS: A total of 418 patients underwent major reconstructive surgery with a mean operating time of 7.5 hours and 12 days' inpatient stay. Cancer (59.8%) and trauma (29.4%) were the most common indications. COVID-19 infection was present in 4.5% of patients. The 30-day post-operative mortality was 0.2%, reflecting the death of one patient who was COVID-negative. Overall complication rate was 20.8%. COVID status did not correlate with major or minor complications. Eight healthcare professionals developed post-operative COVID-19 infection, seven of which occurred within the first three weeks. CONCLUSIONS: Major reconstructive operations performed during the COVID-19 crisis have been mostly urgent cases involving all surgical specialties. This cohort is a surrogate for all major operations across all surgical specialties. Patient safety and surgical outcomes have been the same as in the pre-COVID era. With adequate precautions, major reconstructive surgery is safe for patients and staff. This study helps counsel patients of COVID-19 risks in the perioperative period.

Current perceptions of 'Brazilian butt lift' (BBL) surgery in the UK: A BAAPS-led survey of BAAPS members.

BACKGROUND: The BAAPS advice against Brazilian butt lift (BBL) surgery in the UK was set in October 2018. A Delphi study conducted by BAAPS highlighted the importance of defining current practice and perceptions amongst UK surgeons, as this is currently unknown. OBJECTIVES: To evaluate BAAPS members' current practice and perceptions around BBL surgery to ensure patient safety and propose better recommendations. METHODS: A BAAPS-commissioned survey was emailed to all BAAPS members through an on-line link. The survey collected quantitative and qualitative information in several domains. RESULTS: This survey received a 44% response rate. Of 102 respondents, 32 surgeons undertook BBL surgery before the BAAPS advice to halt it. There was a wide variation in actual fat volumes injected, and in perceptions of what constituted a small or large volume. Virtually all respondents (96.9%) performed only subcutaneous fat injections. There were differences in fat harvest techniques. The majority (66.7%) felt that BAAPS should maintain its recommendation against undertaking BBL surgery until further data became available. Nearly a quarter of 102 respondents (20.6%) had been treated for BBL complications, the majority as a result of surgical tourism. CONCLUSIONS: The survey provides member-reported perception and experience with regard to BBL surgery in the UK. The demand for BBL surgery and its provision should be reassessed in the UK. This information will be analysed with further national and international data to better define and shape the scope of the safety of BBL surgery in the UK. BAAPS will use such data towards the production of future guidance and support for surgeons and patients.

Immediate and delayed autologous abdominal microvascular flap breast reconstruction in patients receiving adjuvant, neoadjuvant or no radiotherapy: a meta-analysis of clinical and quality-of-life outcomes.

BACKGROUND: Effects of postmastectomy radiotherapy (PMRT) on autologous breast reconstruction (BRR) are controversial regarding surgical complications, cosmetic appearance and quality of life (QOL). This systematic review evaluated these outcomes after abdominal free flap reconstruction in patients undergoing postoperative adjuvant radiotherapy (PMRT), preoperative radiotherapy (neoadjuvant radiotherapy) and no radiotherapy, aiming to establish evidence-based optimal timings for radiotherapy and BRR to guide contemporary management. METHODS: The study was registered on PROSPERO (CRD42017077945). Embase, MEDLINE, Google Scholar, CENTRAL, Science Citation Index and ClinicalTrials.gov were searched (January 2000 to August 2018). Study quality and risk of bias were assessed using GRADE and Cochrane's ROBINS-I respectively. RESULTS: Some 12 studies were identified, involving 1756 patients (350 PMRT, 683 no radiotherapy and 723 neoadjuvant radiotherapy), with a mean follow-up of 27·1 (range 12·0-54·0) months for those having PMRT, 16·8 (1·0-50·3) months for neoadjuvant radiotherapy, and 18·3 (1·0-48·7) months for no radiotherapy. Three prospective and nine retrospective cohorts were included. There were no randomized studies. Five comparative radiotherapy studies evaluated PMRT and four assessed neoadjuvant radiotherapy. Studies were of low quality, with moderate to serious risk of bias. Severe complications were similar between the groups: PMRT versus no radiotherapy (92 versus 141 patients respectively; odds ratio (OR) 2·35, 95 per cent c.i. 0·63 to 8·81, P = 0·200); neoadjuvant radiotherapy versus no radiotherapy (180 versus 392 patients; OR 1·24, 0·76 to 2·04, P = 0·390); and combined PMRT plus neoadjuvant radiotherapy versus no radiotherapy (272 versus 453 patients; OR 1·38, 0·83 to 2·32, P = 0·220). QOL and cosmetic studies used inconsistent methodologies. CONCLUSION: Evidence is conflicting and study quality was poor, limiting recommendations for the timing of autologous BRR and radiotherapy. The impact of PMRT and neoadjuvant radiotherapy appeared to be similar.

ANTECEDENTES: En pacientes sometidas a una reconstrucción mamaria (breast reconstruction, BRR) con tejido autólogo se discuten los efectos de la radioterapia post-mastectomía (post-mastectomy radiotherapy, PMRT) en las complicaciones quirúrgicas, el resultado estético y la calidad de vida (quality of life, QOL). Esta revisión sistemática evaluó dichos resultados tras una reconstrucción mamaria con un colgajo libre abdominal en pacientes tratadas con PMRT, radioterapia preoperatoria (Neo RT) y sin radioterapia (RT), a fin de establecer los momentos óptimos de la RT y BRR basados en la evidencia, como guía del tratamiento actual. MÉTODOS: El estudio se registró en la base de datos PROSPERO (CRD42017077945). Se realizaron búsquedas en Embase, MEDLINE, Google Scholar, CENTRAL, Science Citation Index y Clinicaltrials.gov (enero de 2000-agosto de 2018). La calidad de los estudios y el riesgo de sesgo se evaluaron mediante las herramientas GRADE y ROBINS-I de la Cochrane, respectivamente. RESULTADOS: Se identificaron 12 estudios que incluían 1.756 pacientes (350 PMRT, 683 sin RT y 723 Neo RT), con una mediana de seguimiento de 27,1 meses (rango 12,0-54,0) para PMRT, 16,8 meses (1,0-50,3) para Neo RT y 18,3 meses (1,0-48,7) para sin RT. Se incluyeron tres cohortes prospectivas y nueve retrospectivas. No hubo estudios aleatorizados. Los estudios comparativos de RT evaluaron la PMRT (n = 5) y la Neo RT (n = 4). Todos los estudios fueron de baja calidad, con riesgos de sesgo de moderados a graves. Las complicaciones graves fueron similares entre los grupos: PMRT (n = 92) versus sin RT (n = 141), razón de oportunidades (odds ratio, OR) 2,35, i.c. del 95% 0,63-8,81), P = 0,200; Neo RT (n = 180) versus no RT (n = 392) (OR 1,24, i.c. del 95% 0,76-2,04), P = 0,390; o RT combinada (PMRT y neoadyuvante) (n = 272) versus no RT (n = 453) (OR 1,38, i.c. del 95% 0,83-2,32), P = 0,220. Los estudios de calidad de vida y de resultados estéticos utilizaron metodologías poco consistentes. CONCLUSIÓN: La evidencia es contradictoria y la calidad de los estudios muy pobre, hechos que limitan las posibles recomendaciones para el momento de la BRR con tejido autólogo y la RT. El impacto de la PMRT o la Neo RT parecen ser similares.

Adipose derived stem cells and platelet rich plasma improve the tissue integration and angiogenesis of biodegradable scaffolds for soft tissue regeneration.

Current surgical reconstruction for soft tissue replacement involves lipotransfer to restore soft tissue replacements but is limited by survival and longevity of the fat tissue. Alternative approaches to overcome these limitations include using biodegradable scaffolds with stem cells with growth factors to generate soft tissue. Adipose derived stem cells (ADSCs) offer great potential to differentiate into adipose, and can be delivered using biodegradable scaffolds. However, the optimal scaffold to maximise this approach is unknown. This study investigates the biocompatibility of nanocomposite scaffolds (POSS-PCL) to deliver ADSCs with and without the addition of growth factors using platelet rich plasma (PRP) in vivo. Rat ADSCs were isolated and then seeded on biodegradable scaffolds (POSS-PCL). In addition, donor rats were used to isolate PRP to modify the scaffolds. The implants were then subcutaneously implanted for 3-months to assess the effect of PRP and ADSC on POSS-PCL scaffolds biocompatibility. Histology after explanation was examined to assess tissue integration (H&E) and collagen production (Massons Trichome). Immunohistochemistry was used to assess angiogenesis (CD3, α-SMA), immune response (CD45, CD68) and adipose formation (PPAR-γ). At 3-months PRP-ADSC-POSS-PCL scaffolds demonstrated significantly increased tissue integration and angiogenesis compared to PRP, ADSC and unmodified scaffolds (p < 0.05). In addition, PRP-ADSC-POSS-PCL scaffolds showed similar levels of CD45 and CD68 staining compared to unmodified scaffolds. Furthermore, there was increased PPAR-γ staining demonstrated at 3-months with PRP-ADSC-POSS-PCL scaffolds (p < 0.05). POSS-PCL nanocomposite scaffolds provide an effective delivery system for ADSCs. PRP and ADSC work synergistically to enhance the biocompatibility of POSS-PCL scaffolds and provide a platform technology for soft tissue regeneration.

Meta-analysis of venous anastomosis techniques in free flap reconstruction.

BACKGROUND: Coupler devices and hand-sewn anastomosis techniques are both routinely employed for venous anastomosis in microsurgical free flap transfer. However, uncertainty remains about whether those two techniques are different in terms of risk of venous thrombosis. The aim of this review was to evaluate the quality of the evidence and quantify the difference in venous thrombosis rates in both techniques. METHOD: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses compliant systematic review and meta-analysis were performed according to a previously published protocol. MEDLINE and Embase databases were searched from inception to 1 October 2018. Clinical studies using coupler devices for venous anastomoses in free tissue transfer were included. The primary outcome was post-operative venous thrombosis risk. Surgical anastomosis time was a secondary outcome. The risk of bias was assessed with the ROBINS-I or NIH tool and recommendations were made using the GRADE criteria. RESULTS: A total of 10,851 patients across 32 observational retrospective studies were included, with data available for 12,769 free flaps in breast, head and neck, limb and other reconstructions. Direct comparison meta-analysis of 7 studies showed a reduced post-operative thrombosis risk for venous coupler, although this was an imprecise estimate (RR 0.68 [95% CI 0.39-1.19]). The risk of bias was consistently high across all studies. CONCLUSION: Venous couplers may reduce the risk of venous thrombosis, but further randomised trial data are needed to improve the accuracy of this estimate. Further research should also assess size-mismatch between donor and recipient vessel, and the influence of coupler size on outcomes (PROSPERO registration ID: CRD42018110111).

Surgical intervention for chronic migraine headache: A systematic review.

AIMS: Migraine is a global phenomenon, affecting more than 10% of the world's population. It is characterized by unilateral headache that may be accompanied by vomiting, nausea, photophobia and phonophobia. Some patients with chronic migraine respond to extra-cranial botulinum toxin type A injection, although the benefits observed are temporary. The rationale for surgical trigger site deactivation is to achieve lasting symptomatic improvement or permanent relief from migraine. METHODS: We performed a PRISMA-compliant systematic review of clinical studies evaluating surgical intervention for migraine by searching Ovid MEDLINE and EMBASE databases from inception to June 2017. Studies were independently screened by two authors. Data were extracted on study characteristics, migraine outcomes, adverse events and recurrence. The quality of evidence was assessed using the GRADE approach. The review protocol was prospectively registered on the PROSPERO database (CRD42017068577). RESULTS: The search strategy identified 789 articles; of them, 18 studies (4 RCTs and 14 case series) were eligible for analysis. Surgical interventions were heterogeneous and variably involved peripheral nerve decompression by myectomy or foraminotomy, nerve excision, artery resection and/or nasal surgery. All studies reported significant reductions in migraine intensity, frequency, duration and composite headache scores following surgery. Study heterogeneity precluded formal meta-analysis. Where reported, adverse event rates varied markedly between studies. The quality of included studies was consistently low or very low. CONCLUSION: There is insufficient evidence to support the effectiveness of any specific surgical intervention for chronic migraine, especially with regard to permanent relief; however, all included studies report improvements in key outcomes following migraine surgery. A definitive, well-powered RCT with objective surgical and patient-reported outcome measures and robust adverse event reporting is required.

Systematic review of methodologies used to assess mastectomy flap viability.

BACKGROUND: Accurate prediction of mastectomy skin flap viability is vital as necrosis causes significant morbidity, potentially compromising results and delaying oncological management. Traditionally assessed by clinical judgement, a more objective evaluation can be provided using intraoperative imaging modalities. This systematic review aimed to compare all intraoperative techniques for assessment of mastectomy flap viability. METHODS: A systematic literature review was performed using MEDLINE and Embase databases. Primary outcomes reported included specificity, sensitivity and predictive values of each test, and mean rates of mastectomy flap necrosis and reoperation. Secondary outcomes included cost analysis. RESULTS: Some 18 studies were included. Designs were prospective cohort study (8), retrospective case series (4), prospective case series (3), retrospective case-control study (1), prospective pilot trial (1) and cost analysis study (1). The studies compared indocyanine green angiography (ICGA) (16 studies) and fluorescein dye angiography (FA) (3 studies) with clinical judgement. Sensitivity and specificity were highest for ICGA (5 studies) ranging from 38 to 100 and 68 to 91 per cent respectively. Both methods overpredicted necrosis. Mean rates of flap necrosis and reoperation decreased with ICGA (7·9 and 5·5 per cent respectively) and FA (3 and 0 per cent) compared with clinical judgement (19·4 and 12·9 per cent). Two studies were designed to define numerical parameters corresponding to perfusion using intraoperative techniques. Two studies performed a cost analysis for ICGA; one claimed a cost benefit and the other advocated its use in high-risk patients only. CONCLUSION: ICGA and FA are potentially useful tools for mastectomy flap assessment. However, the predictive accuracy is subject to the specific settings and model of equipment used. Current recommendations support their use in high-risk patients.

Upregulation of epidermal gap junctional proteins in patients with venous disease.

BACKGROUND: Leg ulceration is a feared complication of venous insufficiency. It is not known whether varicose veins predispose skin to poor wound healing. The expression pattern of gap junctional protein connexin, a known marker of poor wound healing, was investigated across various stages of venous disease. METHODS: Patients undergoing intervention for varicose veins were assessed according to the Clinical Etiologic Anatomic Pathophysiologic (CEAP) classification of varicose veins. Paired 4-mm punch biopsies were taken from above the ankle (pathological) and above the knee (control). Tissues were stained with haematoxylin and eosin, and for connexin 43, connexin 30 and connexin 26. RESULTS: Forty-eight paired biopsies were taken (12 each for CEAP class C0, C2, C4 and C6). The pathological skin showed progressive epithelial hyperthickening, an increase in the number and depth of rete ridges, increased inflammation and loss of dermal architecture with disease progression from C4 onwards. The overall absolute connexin expression and mean connexin expression per cell in the pathological skin similarly increased across the CEAP classes from as early as C2. Increasing levels of connexin in control skin were also noted, indicating progression of the disease proximally. Connexin 43 expression showed the strongest positive correlation between pathological and control skin. CONCLUSION: Connexins were overexpressed in patients with simple varicose veins, with a stepwise increased expression through venous eczema to ulceration. Connexin 43 is a potential biomarker for venous disease. This finding suggests that varicose veins predispose skin to poor wound healing. Surgical relevance The overexpression of connexins, a family of gap junctional proteins, is known to cause poor healing in venous leg ulceration. It is not known whether there is any association with superficial venous disease. Here, connexin proteins were overexpressed in patients with uncomplicated varicose veins, before histological skin changes. Connexin could be a biomarker of venous disease progression.

Reconstruction of perineal defects.

INTRODUCTION: Perineal defects are commonly encountered in an oncological setting although they may also present as a result of trauma and infection (eg following Fournier's gangrene). Reconstruction of these poses functional as well as aesthetic challenges. Skin coverage and tissue volume may both be required in addition to anogenital preservation or reconstruction. General prerequisites of an adequate reconstruction of perineal defects include provision of skin cover, well vascularised tissue to fill the dead space (reducing fluid collection and infection), vulvovaginal reconstruction and no faecal or urinary contamination. METHODS: A literature search was performed using PubMed and MEDLINE ® . The search terms included 'perineal defects', 'perineal reconstruction', 'perforator flaps for perineum', 'vulval flaps', 'secondary healing of wound' and 'vacuum assisted closure'. Backward chaining of reference lists from retrieved papers was also used to expand the search. FINDINGS: Modern developments have led to an increased expectation in improved quality of life as the main goal of reconstruction, therefore necessitating surgery with less morbidity and early return to normal activity. Progress in microsurgical procedures has been the main recent advance in perineal reconstruction and, in future, refinements in perforator flap design and tissue engineering techniques will lead to even better reconstructions.