A Scoping Review of Innervated Breast Reconstruction.

BACKGROUND: After breast surgery, patients experience significant alterations to breast sensation, which can diminish quality of life. Nerve coaptation technique, introduced in the 1990s, has gained traction in recent years. We performed a scoping review of the literature to determine the available outcomes in sensate breast reconstruction. METHODS: The review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews statement guidelines. EMBASE and PubMed databases were queried using standardized terminology. Studies were included if they reported original sensory outcomes following innervation techniques during breast reconstruction and were published from January 1, 1990, to April 18, 2022. Data extraction and analyses were performed on Microsoft Excel. RESULTS: From 602 screened articles, 27 studies met the inclusion criteria. Innervated autologous reconstructive procedures were described in 24, whereas the remaining 3 (all published after 2019) described direct reinnervation of the nipple-areola complex. Most (88.9%) of the studies comparing innervated versus noninnervated reconstruction reported improved sensory outcomes in at least 1 modality. Two studies investigated patient-reported outcomes using validated questionnaires, both of which reported improvement with innervated reconstruction. CONCLUSIONS: Sensate breast reconstruction has the potential to improve outcomes for patients. There is a recent progressive increase in studies involving direct nipple-areolar reinnervation. Larger, prospective studies are needed to better characterize the quality-of-life outcome using validated scales, as well as evaluate sensory and patient-reported outcomes with implant and autologous reconstruction.

Craniometric and Aesthetic Outcomes in Craniosynostosis Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: To systematically review the published comparative aesthetic outcomes, and its determinants, for craniosynostoses surgically treated by minimally-invasive cranial procedures and open cranial vault remodeling (CVR). DESIGN: PRISMA-compliant systematic review. SETTING: Not-applicable. PATIENTS/PARTICIPANTS: Articles were included if they compared spring cranioplasty, strip minimally-invasive craniectomy or CVR for outcomes related to aesthetics or head shape. Forty-two studies were included, comprising 2402 patients. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): The craniometric and PROM used to determine surgical outcomes. RESULTS: Twenty-five studies (59%) evaluated sagittal craniosynostosis, with metopic (7;17%) and unicoronal (4;10%) the next most prevalent. Thirty-eight studies (90%) included CVR, 24 (57%) included strip craniectomy with helmeting, 9 (22%) included strip craniectomy without helmeting, 11 (26%) included spring cranioplasty, and 3 (7%) included vault distraction. A majority of studies only used 1 (43%) or 2 (14%) craniometric measures to compare techniques. In sagittal synostosis, 13 (59%) studies showed no difference in craniometric outcomes, 5 (23%) showed better results with CVR, 3 (14%) with strip craniectomy, and 1 (5%) with springs. In studies describing other synostoses, 10/14 (71%) were equivocal. Subjective outcome measures followed similar trends. Meta-analysis shows no significant difference in cranial index (CI) outcomes between CVR and less invasive procedures in patients with sagittal synostosis. CONCLUSIONS: There is no difference in CI outcomes between CVR and less invasive procedures. The majority of literature comparing craniometric and aesthetic outcomes between CVR and less invasive procedures shows equivocal results for sagittal synostosis. However, the heterogeneity of data for other craniosynostoses did not allow meta-analysis.

Free functional muscle transfer for lower extremity reconstruction.

BACKGROUND: Free functional muscle transfer is a reconstructive strategy for the reconstruction of lost muscle units in the lower extremity after oncologic resection, trauma, compartment syndrome, or severe nerve injuries. Under appropriate circumstances, free functional muscle transfer may be the only suitable reconstructive option. This article reviews the underlying principles of free functional muscle transfer, its application to lower extremity reconstruction, appropriate patient selection, and surgical techniques. METHODS: The underlying principles of free functional muscle transfer, its application to lower extremity reconstruction, appropriate patient selection, and surgical techniques are presented. Commonly used donor muscles appropriate for each type of functional defect are discussed. A review of recent publications on free functional muscle transfer in the lower extremity was also performed. RESULTS: Good functional recovery with a Medical Research Council grade of up to 4/5 and full range of motion can be attained with free functional muscle transfer. Clinical outcomes and specific parameters for published case series in lower extremity free functional muscle transfer are presented and an illustrative case. CONCLUSION: Free functional muscle transfer is a suitable treatment for the appropriate patient to restore essential functions and potentially regain ambulation. However, additional published clinical outcomes are needed and represent a major area for further investigation.

Stopping Traffic: An Analysis of Number of Scrubbed Personnel and Infection in Implant-Based Breast Reconstruction.

BACKGROUND: Postoperative surgical site infection (SSI) is a devastating complication of implant-based breast reconstruction. Its occurrence may require additional hospitalization and ultimately necessitate prosthesis removal. The effect of foot traffic in the operating room has not yet been investigated within plastic surgery. OBJECTIVES: This study analyzed the influence of scrubbed and unscrubbed personnel on postoperative SSI in immediate implant-based breast reconstruction. METHODS: This was a retrospective review of 223 consecutive patients who underwent immediate implant-based reconstruction from 2015 to 2021 at the authors' institution. Patient demographics, comorbidities, smoking status, laterality, number of personnel, use of drains, and length of surgery were collected. The primary outcome assessed was surgical site infection with secondary outcomes of delayed wound healing, skin necrosis, hematoma, seroma, and reoperation within 90 days. RESULTS: Patients who had a postoperative SSI had a mean number of 8.7 scrubbed individuals, whereas those who did not have a postoperative SSI had a mean number of 7.9 individuals scrubbed (P < .05). Univariate analysis demonstrated that increasing number of scrubbed individuals was predictive of SSI (odds ratio [OR]: 1.239, CI: 1.064-1.444, P < .05). A multivariate logistic regression demonstrated increased likelihood of SSI with increasing number of individuals scrubbed (OR: 1.232, CI: 1.027-1.478, P < .05). CONCLUSIONS: This study demonstrates an increased risk of SSI in immediate, implant-based breast reconstruction with an increased number of personnel in the operative field. The findings highlight the importance of reducing foot traffic in the operating room when feasible to reduce risk of postoperative SSI and its associated morbidity.

Potential Effects of Repetitive Panfacial Filler Injections on Facelift Surgery and Surgical Outcomes: Survey Results of the Members of The Aesthetic Society.

Background: Facial soft-tissue filler injections are being performed in the United States with increasing popularity.f. Objectives: This study aimed to characterize the observations of The Aesthetic Society members regarding the potential impact of repetitive panfacial fillers on the outcomes of subsequent facelift surgery. Methods: A survey containing closed and open-ended questions was sent to The Aesthetic Society members through email. Results: The response rate was 3.7%. The majority of the respondents (80.8%) believed that less than 60% of their facelift patients had previous repetitive panfacial filler injections. One half (51.9%) reported that a history of panfacial filler injections increased the difficulty of performing facelifts. A large subset (39.7%) of respondents believed that a history of panfacial fillers increased postoperative complication rates, while the remaining either disagreed (28.9%) or were unsure (31.4%). The most common complications following the facelift surgery included undesirable palpability or visibility of filler (32.7%), compromised flap vascularity (15.4%), and decreased longevity of the lifting effect (9.6%). Conclusions: This study identified a potential association with repetitive panfacial filler injections and outcomes following facelift surgery, although the exact effect on postoperative outcomes remains unclear. Large prospectively designed studies are needed to capture objective data comparing facelift patients with a history of repetitive panfacial fillers with those facelift patients who have never had injectables. Given the results of The Aesthetic Society members' survey, the authors encourage careful history-taking to elicit an accurate filler injection record including complications after filler injections, as well as engaging patients in a thorough preoperative discussion regarding the potential of panfacial fillers on the facelift procedure and postoperative outcomes.

Evaluation of an Adoptive Cellular Therapy-Based Vaccine in a Transgenic Mouse Model of α-synucleinopathy.

Aggregated α-synuclein, a major constituent of Lewy bodies plays a crucial role in the pathogenesis of α-synucleinopathies (SPs) such as Parkinson's disease (PD). PD is affected by the innate and adaptive arms of the immune system, and recently both active and passive immunotherapies targeted against α-synuclein are being trialed as potential novel treatment strategies. Specifically, dendritic cell-based vaccines have shown to be an effective treatment for SPs in animal models. Here, we report on the development of adoptive cellular therapy (ACT) for SP and demonstrate that adoptive transfer of pre-activated T-cells generated from immunized mice can improve survival and behavior, reduce brain microstructural impairment via magnetic resonance imaging (MRI), and decrease α-synuclein pathology burden in a peripherally induced preclinical SP model (M83) when administered prior to disease onset. This study provides preclinical evidence for ACT as a potential immunotherapy for LBD, PD and other related SPs, and future work will provide necessary understanding of the mechanisms of its action.

From Mouth to Muscle: Exploring the Potential Relationship between the Oral Microbiome and Cancer-Related Cachexia.

Cancer cachexia is a multifactorial wasting syndrome associated with skeletal muscle and adipose tissue loss, as well as decreased appetite. It affects approximately half of all cancer patients and leads to a decrease in treatment efficacy, quality of life, and survival. The human microbiota has been implicated in the onset and propagation of cancer cachexia. Dysbiosis, or the imbalance of the microbial communities, may lead to chronic systemic inflammation and contribute to the clinical phenotype of cachexia. Though the relationship between the gut microbiome, inflammation, and cachexia has been previously studied, the oral microbiome remains largely unexplored. As the initial point of digestion, the oral microbiome plays an important role in regulating systemic health. Oral dysbiosis leads to the upregulation of pro-inflammatory cytokines and an imbalance in natural flora, which in turn may contribute to muscle wasting associated with cachexia. Reinstating this equilibrium with the use of prebiotics and probiotics has the potential to improve the quality of life for patients suffering from cancer-related cachexia.

One Size Does Not Fit All; Patient Preference for Breast Reconstruction.

Background: A myriad of patient education modalities for breast reconstruction exist, although the optimal tools for patient education remain undetermined. The aim of this study is to determine patient preferences for breast reconstruction education modalities based on demographic variables. Methods: A prospective observational study at a tertiary care university health system was conducted between November 2020 and May 2021. A questionnaire was administered to breast reconstruction patients to collect information on demographics, research sources used before the initial appointment, and preferred education modalities. Differences based on age were analyzed using an independent samples t test, whereas a Fisher exact test was used to analyze differences based on ethnicity and education level. Statistical significance was defined as P < .05. Results: The most preferred patient education tools overall were books/written materials and videos. Younger patients were significantly more likely than older patients to have referenced additional physician sources (P = .0174) and to seek out information on the institution's website (P = .0465). Those with a college degree were significantly more likely to have performed research prior to the initial appointment (P = .0206). White patients were significantly more likely than nonwhite patients to talk to friends/family as a research source (P = .0150). Conclusions: Regardless of age, education, or ethnicity, most patients prefer books/written materials and video presentations for education on breast reconstruction. Providers should strive to include written and video options to meet the needs of this diverse patient population.

Combined pectoralis and rectus abdominis flaps are associated with improved outcomes in sternal reconstruction.

BACKGROUND: Mortality increases nearly 5-fold in the approximately 5% of patients who develop sternal wound complications after cardiothoracic surgery. Flap-based reconstruction can improve outcomes by providing well-vascularized soft tissue for potential space obliteration, antibiotic delivery, and wound coverage; however, reoperation and readmission rates remain high. This study used the high case volume at a tertiary referral center and a diverse range of reconstructive approaches to compare various types of flap reconstruction. Combined (pectoralis and rectus abdominis) flap reconstruction is hypothesized to decrease sternal wound complication-related adverse outcomes. METHODS: A retrospective cohort study of consecutive adult patients treated for cardiothoracic surgery sternal wound complications between 2008 and 2018 was performed. Patient demographics, comorbidities, wound characteristics, surgical parameters, and perioperative data were collected. Multivariable regression modeling with stepwise forward selection was used to characterize predictive factors for sternal wound-related readmissions and reoperations. RESULTS: In total, 215 patients were assessed for sternal wound reconstruction. Patient mortality at 1 year was 12.4%. Flap selection was significantly associated with sternal wound-related readmissions (P = .017) and reoperations (P = .014). Multivariate regression demonstrated rectus abdominis flap reconstruction independently predicted increased readmissions (odds ratio 3.4, P = .008) and reoperations (odds ratio 2.9, P = .038). Combined pectoralis and rectus abdominis flap reconstruction independently predicted decreased readmissions overall (odds ratio 0.4, P = .031) and in the deep sternal wound subgroup (odds ratio 0.1, P = .033). CONCLUSION: Although few factors can be modified in this complex highly comorbid population with a challenging and rare surgical problem, consideration of a more surgically aggressive multiflap reconstructive approach may be justified to improve outcomes.

CXCR2 inhibition enables NASH-HCC immunotherapy.

OBJECTIVE: Hepatocellular carcinoma (HCC) is increasingly associated with non-alcoholic steatohepatitis (NASH). HCC immunotherapy offers great promise; however, recent data suggests NASH-HCC may be less sensitive to conventional immune checkpoint inhibition (ICI). We hypothesised that targeting neutrophils using a CXCR2 small molecule inhibitor may sensitise NASH-HCC to ICI therapy. DESIGN: Neutrophil infiltration was characterised in human HCC and mouse models of HCC. Late-stage intervention with anti-PD1 and/or a CXCR2 inhibitor was performed in murine models of NASH-HCC. The tumour immune microenvironment was characterised by imaging mass cytometry, RNA-seq and flow cytometry. RESULTS: Neutrophils expressing CXCR2, a receptor crucial to neutrophil recruitment in acute-injury, are highly represented in human NASH-HCC. In models of NASH-HCC lacking response to ICI, the combination of a CXCR2 antagonist with anti-PD1 suppressed tumour burden and extended survival. Combination therapy increased intratumoural XCR1+ dendritic cell activation and CD8+ T cell numbers which are associated with anti-tumoural immunity, this was confirmed by loss of therapeutic effect on genetic impairment of myeloid cell recruitment, neutralisation of the XCR1-ligand XCL1 or depletion of CD8+ T cells. Therapeutic benefit was accompanied by an unexpected increase in tumour-associated neutrophils (TANs) which switched from a protumour to anti-tumour progenitor-like neutrophil phenotype. Reprogrammed TANs were found in direct contact with CD8+ T cells in clusters that were enriched for the cytotoxic anti-tumoural protease granzyme B. Neutrophil reprogramming was not observed in the circulation indicative of the combination therapy selectively influencing TANs. CONCLUSION: CXCR2-inhibition induces reprogramming of the tumour immune microenvironment that promotes ICI in NASH-HCC.

COVID-19 and liver cancer: lost patients and larger tumours.

BACKGROUND: Northern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region. OBJECTIVE: To assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region. DESIGN: We prospectively audited our service for the first year of the pandemic (March 2020-February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019-February 2020). RESULTS: We observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection. CONCLUSION: The pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage.

The History and Innovations of Blood Vessel Anastomosis.

Surgical technique and technology frequently coevolve. The brief history of blood vessel anastomosis is full of famous names. While the techniques pioneered by these surgeons have been well described, the technology that facilitated their advancements and their inventors deserve recognition. The mass production of laboratory microscopes in the mid-1800s allowed for an explosion of interest in tissue histology. This improved understanding of vascular physiology and thrombosis laid the groundwork for Carrel and Guthrie to report some of the first successful vascular anastomoses. In 1916, McLean discovered heparin. Twenty-four years later, Gordon Murray found that it could prevent thrombosis when performing end-to-end anastomosis. These discoveries paved the way for the first-in-human kidney transplantations. Otolaryngologists Nylen and Holmgren were the first to bring the laboratory microscope into the operating room, but Jacobson was the first to apply these techniques to microvascular anastomosis. His first successful attempt in 1960 and the subsequent development of microsurgical tools allowed for an explosion of interest in microsurgery, and several decades of innovation followed. Today, new advancements promise to make microvascular and vascular surgery faster, cheaper, and safer for patients. The future of surgery will always be inextricably tied to the creativity and vision of its innovators.

Human urine-derived renal epithelial cells provide insights into kidney-specific alternate splicing variants.

The majority of multi-exon genes undergo alternative splicing to produce different mRNA transcripts and this may occur in a tissue-specific manner. Assessment of mRNA transcripts isolated from blood samples may sometimes be unhelpful in determining the affect on function of putative splice-site variants affecting kidney-specific mRNA transcripts. Here we present data demonstrating the power of using human urine-derived renal epithelial cells (hUREC) as a source of kidney RNA. We report clinical and molecular genetic data from three affected cases from two families all with end-stage renal disease by 15 years of age. In both families, heterozygous variants which are predicted to effect function in NPHP3 were found on one allele, in combination with a synonymous SNV (c.2154C>T; p.Phe718=), 18 base pairs from the exon-intron boundary within exon 15 of NPHP3. The only mRNA transcript amplified from wild-type whole blood showed complete splicing out of exon 15. Urine samples obtained from control subjects and the father of family 2, who carried the synonymous SNV variant, were therefore used to culture hUREC and allowed us to obtain kidney-specific mRNA. Control kidney mRNA showed retention of exon 15, while the mRNA from the patient's father confirmed evidence of a heterozygous alternate splicing of exon 15 of NPHP3. Analysis of RNA derived from hUREC allows for a comparison of kidney-specific and whole-blood RNA transcripts and for assessment of the effect on function of putative splice variants leading to end-stage kidney disease.

l-Carnitine Inhibits Lipopolysaccharide-Induced Nitric Oxide Production of SIM-A9 Microglia Cells.

Microglia are the resident immune effector cells of the central nervous system. They account for approximately 10-15% of all cells found in the brain and spinal cord, acting as macrophages, sensing and engaging in phagocytosis to eliminate toxic proteins. Microglia are dynamic and can change their morphology in response to cues from their milieu. Parkinson's disease is a neurodegenerative disease, associated with reactive gliosis, neuroinflammation, and oxidative stress. It is thought that Parkinson's disease is caused by the accumulation of abnormally folded alpha-synuclein protein, accompanied by persistent neuroinflammation, oxidative stress, and subsequent neuronal injury/death. There is evidence in the literature for mitochondrial dysfunction in Parkinson's disease as well as fatty acid beta-oxidation, involving l-carnitine. Here we investigate l-carnitine in the context of microglial activation, suggesting a potential new strategy of supplementation for PD patients. Preliminary results from our studies suggest that the treatment of activated microglia with the endogenous antioxidant l-carnitine can reverse the effects of detrimental neuroinflammation in vitro.

Many Genes-One Disease? Genetics of Nephronophthisis (NPHP) and NPHP-Associated Disorders.

Nephronophthisis (NPHP) is a renal ciliopathy and an autosomal recessive cause of cystic kidney disease, renal fibrosis, and end-stage renal failure, affecting children and young adults. Molecular genetic studies have identified more than 20 genes underlying this disorder, whose protein products are all related to cilia, centrosome, or mitotic spindle function. In around 15% of cases, there are additional features of a ciliopathy syndrome, including retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. Alongside, gene identification has arisen molecular mechanistic insights into the disease pathogenesis. The genetic causes of NPHP are discussed in terms of how they help us to define treatable disease pathways including the cyclic adenosine monophosphate pathway, the mTOR pathway, Hedgehog signaling pathways, and DNA damage response pathways. While the underlying pathology of the many types of NPHP remains similar, the defined disease mechanisms are diverse, and a personalized medicine approach for therapy in NPHP patients is likely to be required.

A novel LMX1B mutation in a family with end-stage renal disease of 'unknown cause'.

End-stage renal disease (ESRD) presenting in a familial autosomal dominant pattern points to an underlying monogenic cause. Nail-patella syndrome (NPS) is an autosomal dominant disorder that may lead to ESRD caused by mutations in the transcription factor LMX1B. Renal-limited forms of this disease, termed nail-patella-like renal disease (NPLRD), and LMX1B nephropathy have recently been described. We report a large family, from the North East of England, with seven affected members with varying phenotypes of renal disease, ranging from ESRD at 28 years of age to microscopic haematuria and proteinuria and relatively preserved renal function. In this family, there were no extra-renal manifestations to suggest NPS. Genome-wide linkage studies and inheritance by descent (IBD) suggested disease loci on Chromosome 1 and 9. Whole exome sequencing (WES) analysis identified a novel sequence variant (p.R249Q) in the LMX1B gene in each of the three samples submitted, which was confirmed using Sanger sequencing. The variant segregated with the disease in all affected individuals. In silico modelling revealed that R249 is putatively located in close proximity to the DNA phosphoskeleton, supporting a role for this residue in the interaction between the LMX1B homeodomain and its target DNA. WES and analysis of potential target genes, including CD2AP, NPHS2, COL4A3, COL4A4 and COL4A5, did not reveal any co-inherited pathogenic variants. In conclusion, we confirm a novel LMX1B mutation in a large family with an autosomal dominant pattern of nephropathy. This report confirms that LMX1B mutations may cause a glomerulopathy without extra-renal manifestations. A molecular genetic diagnosis of LMX1B nephropathy thus provides a definitive diagnosis, prevents the need for renal biopsies and allows at risk family members to be screened.

Murine Joubert syndrome reveals Hedgehog signaling defects as a potential therapeutic target for nephronophthisis.

Nephronophthisis (NPHP) is the major cause of pediatric renal failure, yet the disease remains poorly understood, partly due to the lack of appropriate animal models. Joubert syndrome (JBTS) is an inherited ciliopathy giving rise to NPHP with cerebellar vermis aplasia and retinal degeneration. Among patients with JBTS and a cerebello-oculo-renal phenotype, mutations in CEP290 (NPHP6) are the most common genetic lesion. We present a Cep290 gene trap mouse model of JBTS that displays the kidney, eye, and brain abnormalities that define the syndrome. Mutant mice present with cystic kidney disease as neonates. Newborn kidneys contain normal amounts of lymphoid enhancer-binding factor 1 (Lef1) and transcription factor 1 (Tcf1) protein, indicating normal function of the Wnt signaling pathway; however, an increase in the protein Gli3 repressor reveals abnormal Hedgehog (Hh) signaling evident in newborn kidneys. Collecting duct cells from mutant mice have abnormal primary cilia and are unable to form spheroid structures in vitro. Treatment of mutant cells with the Hh agonist purmorphamine restored normal spheroid formation. Renal epithelial cells from a JBTS patient with CEP290 mutations showed similar impairments to spheroid formation that could also be partially rescued by exogenous stimulation of Hh signaling. These data implicate abnormal Hh signaling as the cause of NPHP and suggest that Hh agonists may be exploited therapeutically.

Management of hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is a disease characterized by hemolysis, thrombocytopenia, and acute kidney injury, although other organs may be involved. Most cases are due to infection with Shiga toxin-producing Escherichia coli (STEC). Early identification and initiation of best supportive care, with microbiological input to identify the pathogen, result in a favorable outcome in most patients. The remaining 10% of HUS cases are classed together as atypical HUS and have a diverse etiology. The majority are due to inherited or acquired abnormalities that lead to a failure to control complement activation. Atypical HUS occurring in other situations (for example, related to pregnancy or kidney transplantation) may also involve excessive complement activation. Plasma therapies can reverse defective complement control, and it is now possible to specifically target complement activation. This has led to improved outcomes in patients with atypical forms of HUS. We will review our current understanding of the pathogenesis of HUS and how this has led to advances in patient care.