Mesenchyme governs hair follicle induction.

Tissue interactions are essential for guiding organ development and regeneration. Hair follicle formation relies on inductive signalling between two tissues, the embryonic surface epithelium and the adjacent mesenchyme. Although previous research has highlighted the hair-inducing potential of the mesenchymal component of the hair follicle - the dermal papilla and its precursor, the dermal condensate - the source and nature of the primary inductive signal before dermal condensate formation have remained elusive. Here, we performed epithelial-mesenchymal tissue recombination experiments using hair-forming back skin and glabrous plantar skin from mouse embryos to unveil that the back skin mesenchyme is inductive even before dermal condensate formation. Moreover, the naïve, unpatterned mesenchyme was sufficient to trigger hair follicle formation even in the oral epithelium. Building on previous knowledge, we explored the hair-inductive ability of the Wnt agonist R-spondin 1 and a Bmp receptor inhibitor in embryonic skin explants. Although R-spondin 1 instigated precocious placode-specific transcriptional responses, it was insufficient for hair follicle induction, either alone or in combination with Bmp receptor inhibition. Our findings pave the way for identifying the hair follicle-inducing cue.

Clinical and molecular characterization of limb-girdle muscular dystrophy 2G/R7 in a large cohort of Brazilian patients.

Limb-girdle muscular dystrophy type 2G/R7 (LGMD2G/R7) is an ultra-rare condition initially identified within the Brazilian population. We aimed to expand clinical and genetic information about this disease, including its worldwide distribution. A multicenter historical cohort study was performed at 13 centers in Brazil in which data from index cases and their affected relatives from consecutive families with LGMD2G/R7 were reviewed from July 2017 to August 2023. Additionally, a systematic literature review was conducted to identify case reports and series of the disease worldwide. Forty-one LGMD2G/R7 cases were described in the Brazilian cohort, being all subjects homozygous for the c.157C>T/(p.Gln53*) variant in TCAP. Survival curves showed that the median disease duration before individuals required walking aids was 21 years. Notably, women exhibited a slower disease progression, requiring walking aids 13 years later than men. LGMD2G/R7 was frequently reported not only in Brazil but also in China and Bulgaria, with 119 cases identified globally, with possible founder effects in the Brazilian, Eastern European, and Asian populations. These findings are pivotal in raising awareness of LGMD2G/R7, understanding its progression, and identifying potential modifiers. This can significantly contribute to the development of future natural history studies and clinical trials for this disease.

Did She or Didn't She? Perceptions of Operative Status of Female Genitalia.

BACKGROUND: While extensive research has explored why women undergo labiaplasty, little attention has been paid to societal and professional abilities to distinguish between altered and unaltered labia, impacting both patient concerns and broader societal perceptions. OBJECTIVES: This study aimed to evaluate the accuracy of the general public and healthcare professionals in identifying labiaplasty and to pinpoint the misconceptions driving their perceptions. The goal was to inform more effective patient counseling strategies and challenge existing stigmas around cosmetic genital surgery. METHODS: We conducted an online survey with 511 lay adults and a group of 21 gynecologists and aesthetic vulvar surgeons, assessing their ability to detect labiaplasty from images, focusing on aesthetic appearance, hair patterns, and size. The analysis involved Pearson correlation and Z-tests to compare perceptions against actual operative status. RESULTS: Our analysis revealed a pronounced difficulty among participants in accurately discerning labiaplasty, with neither group showing a significant ability to identify surgical alterations. Misinterpretations were notably influenced by expectations of aesthetic appearance, with 49% associating an "odd" or "fake" look with surgery, and hair and size misconceptions also misleading respondents. Additionally, 20% of participants mistakenly related surgical changes to gender affirming surgery or female genital mutilation. CONCLUSIONS: The study highlights a gap in the ability of both the general public and medical professionals to accurately identify labiaplasty, pointing to a broad misunderstanding of cosmetic genital surgery's visual outcomes. Addressing these misconceptions through targeted education could substantially improve patient counseling and help dismantle the stigmas associated with labiaplasty.

Connexin 43 and cell culture substrate differentially regulate OCY454 osteocytic differentiation and signaling to primary bone cells.

Connexin 43 (Cx43), the predominate gap junction protein in bone, is essential for intercellular communication and skeletal homeostasis. Previous work suggests that osteocyte-specific deletion of Cx43 leads to increased bone formation and resorption; however, the cell-autonomous role of osteocytic Cx43 in promoting increased bone remodeling is unknown. Recent studies using three-dimensional (3D) culture substrates in OCY454 cells suggest that 3D cultures may offer increased bone remodeling factor expression and secretion, such as sclerostin and receptor activator of nuclear factor-κB ligand (RANKL). In this study, we compared culturing OCY454 osteocytes on 3D Alvetex scaffolds with traditional 2D tissue culture, both with [wild-type (WT)] and without Cx43 (Cx43 KO). Conditioned media from OCY454 cell cultures were used to determine soluble signaling to differentiate primary bone marrow cells into osteoblasts and osteoclasts. OCY454 cells cultured on 3D portrayed a mature osteocytic phenotype, relative to cells on 2D, shown by increased osteocytic gene expression and reduced cell proliferation. In contrast, OCY454 differentiation based on these same markers was not affected by Cx43 deficiency in 3D. Interestingly, increased sclerostin secretion was found in 3D cultured WT cells compared with that of Cx43 KO cells. Conditioned media from Cx43 KO cells promoted increased osteoblastogenesis and osteoclastogenesis, with maximal effects from 3D cultured Cx43 KO cells. These results suggest that Cx43 deficiency promotes increased bone remodeling in a cell-autonomous manner with minimal changes in osteocyte differentiation. Finally, 3D cultures appear better suited to study mechanisms from Cx43-deficient OCY454 osteocytes in vitro due to their ability to promote osteocyte differentiation, limit proliferation, and increase bone remodeling factor secretion.NEW & NOTEWORTHY 3D cell culture of OCY454 cells promoted increased differentiation compared with traditional 2D culture. Although Cx43 deficiency did not affect OCY454 differentiation, it resulted in increased signaling, promoting osteoblastogenesis and osteoclastogenesis. Our results suggest that Cx43 deficiency promotes increased bone remodeling in a cell-autonomous manner with minimal changes in osteocyte differentiation. Also, 3D cultures appear better suited to study mechanisms in Cx43-deficient OCY454 osteocytes.

ATG versus PTCy in matched unrelated donor haematopoietic stem cell transplantations with non-myeloablative conditioning.

Graft-versus-host disease (GvHD) is a serious complication of allogeneic haematopoietic stem cell transplantation (HSCT). Both anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) are used as lymphocyte-depleting strategies, yet a systematic comparison of transplantation outcomes between these two methods in matched unrelated donors (MUD) transplantations with non-myeloablative conditioning (NMC) is lacking. Adult patients with haematological malignancies who had undergone MUD HSCT with NMC regimens between 2014 and 2021 at 2 centres in Amsterdam (ATG: n = 95, PTCy: n = 90), were included in this retrospective study. Patient characteristics were comparable between the groups. The cumulative incidence of acute GvHD grade II-IV was 48% in the ATG group compared to 21% in the PTCy group (p < 0.001). The 3-year moderate/severe chronic GvHD was similar in both groups (p = 0.69). While the relapse rate was comparable between the groups (ATG 31% vs. PTCy 34%, p = 0.94), non-relapse mortality tended to be higher in the ATG group (17% vs. 9%, p = 0.069). Overall survival was similar in both groups (p = 0.12). In conclusion, PTCy-based regimens resulted in a significantly lower rate of acute GvHD than ATG-containing regimens in MUD transplantations with NMC. Whether PTCy results in improved overall survival as compared to ATG needs to be elucidated in larger prospective studies.

Utility of a Test-to-Return Strategy to Identify Individuals With Coronavirus Disease 2019 (COVID-19) in the Prekindergarten Through Grade 12 School Setting-District of Columbia, January 2022.

The highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant led to increased hospitalizations, staffing shortages, and increased school closures. To reduce spread in school-aged children during the Omicron peak, the District of Columbia implemented a test-to-return strategy in public and public charter schools after a 2-week break from in-person learning.

Labiaplasty: The Stigma Persists.

BACKGROUND: Heightening interest in labiaplasty has driven potential patients to online fora, permitting the dissemination of material by potentially unqualified or inexperienced individuals. The discourse surrounding this procedure has been injected with strong opinions that are not entirely consistent with medical best-practice or evidence-based knowledge. OBJECTIVES: The aim of this study was to explore the rationale for ongoing public opposition to labiaplasty and to investigate if awareness of the similarities between labiaplasty and breast reduction can alter an individual's perception. METHODS: Four hundred and forty-eight adult women were surveyed concerning their opinion of a surgical procedure to reduce the size of an unspecified organ related to a woman's sexuality, breast reduction, and labia reduction. RESULTS: Reduction of an unspecified organ and breasts was met with significantly greater acceptance than labia reduction (P < 0.0001). Presenting responders with an educational tool comparing each procedure's indications, risks, and potential benefits did not alter respondent opinions, indicating notions about sexual surgery are relatively fixed. The most common reason respondents persisted in their relative opposition to labia reduction was a perceived deficiency in social acceptance (27.1%), followed by a perceived similarity to female genital mutilation (14.8%). CONCLUSIONS: Attitudes towards labiaplasty seem firmly based on emotion or correlation to other unacceptable practices. Informational resources do not sway these biases; thus, there is a limited role for surgeon-led education in the normalization of labiaplasty because it requires a societal shift in acceptance. Labiaplasty is a procedure whose time for popular acceptance has not yet come.

Incidence of Obstetric Lacerations and Episiotomy Following Labiaplasty.

BACKGROUND: A significant proportion of patients seeking labiaplasty are nulliparous and may experience later changes to their labia following vaginal delivery. OBJECTIVES: In the present study, the authors reported the long-term outcomes of a single surgeon's patient cohort who had vaginal delivery after labiaplasty. METHODS: A retrospective chart review of the senior author's database was conducted. All patients who underwent in-office labiaplasty from 2007 to 2018 were surveyed. The resulting cohort was stratified into patients who had delivered children prior to labiaplasty and those who delivered after labiaplasty. RESULTS: A total of 204 patients responded to a phone survey. Seventy patients had children prior to undergoing labiaplasty, and 33 had children after labiaplasty. The rate of vaginal delivery was lower in the women who had children before labiaplasty (82.6% vs 91.8%, P = 0.015). The tear/episiotomy rate for vaginal deliveries was lower in women who had children prior to labiaplasty compared with after labiaplasty (3.1% vs 17.8%, P < 0.001). Among the women who had children only after labiaplasty, the reported tear/episiotomy rate was 7/39 vaginal deliveries (17.9%). CONCLUSION: Patients in our cohort had over 90% success with vaginal deliveries after labiaplasty. For nulliparous patients contemplating the procedure, the data we present suggest the risk of episiotomy or vaginal tear risk with vaginal birth after labiaplasty is comparable with or lower than the general population, further supporting the safety of this procedure. For patients with previous delivery, the data are more limited but suggest no increased risk in this small cohort.

Vemurafenib in non-small-cell lung cancer patients with BRAFV600 and BRAFnonV600 mutations.

BACKGROUND: BRAF mutations occurring in 1%-5% of patients with non-small-cell lung cancer (NSCLC) are therapeutic targets for these cancers but the impact of the exact mutation on clinical activity is unclear. The French National Cancer Institute (INCA) launched the AcSé vemurafenib trial to assess the efficacy and safety of vemurafenib in cancers with various BRAF mutations. We herein report the results of the NSCLC cohort. PATIENTS AND METHODS: Tumour samples were screened for BRAF mutations in INCA-certified molecular genetic centres. Patients with BRAF-mutated tumours progressing after ≥1 line of treatment were proposed vemurafenib 960 mg twice daily. Between October 2014 and July 2018, 118 patients were enrolled in the NSCLC cohort. The primary outcome was the objective response rate (ORR) assessed every 8 weeks (RECIST v1.1). A sequential Bayesian approach was planned with an inefficacy bound of 10% for ORR. If no early stopping occurred, the treatment was of interest if the estimated ORR was ≥30% with a 90% probability. Secondary outcomes were tolerance, response duration, progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 118 patients enrolled, 101 presented with a BRAFV600 mutation and 17 with BRAFnonV600 mutations; the median follow-up was 23.9 months. In the BRAFnonV600 cohort, no objective response was observed and this cohort was stopped. In the BRAFV600 cohort, 43/96 patients had objective responses. The mean Bayesian estimated success rate was 44.9% [95% confidence intervals (CI) 35.2%-54.8%]. The ORR had a 99.9% probability of being ≥30%. Median response duration was 6.4 months, median PFS was 5.2 months (95% CI 3.8-6.8), and OS was 10 months (95% CI 6.8-15.7). The vemurafenib safety profile was consistent with previous publications. CONCLUSION: Routine biomarker screening of NSCLC should include BRAFV600 mutations. Vemurafenib monotherapy is effective for treating patients with BRAFV600-mutated NSCLC but not those with BRAFnonV600 mutations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02304809.

18FDG PET/CT in the early assessment of non-small cell lung cancer response to immunotherapy: frequency and clinical significance of atypical evolutive patterns.

PURPOSE: This prospective study aimed (1) to assess the non-small cell lung cancer (NSCLC) evolutive patterns to immunotherapy using FDG-PET and (2) to describe their association with clinical outcome. DESIGN: Fifty patients with metastatic NSCLC were included before pembrolizumab or nivolumab initiation. FDG-PET scan was performed at baseline and after 7 weeks of treatment (PETinterim1) and different criteria/parameters of tumor response were assessed, including PET response criteria in solid tumors (PERCIST). If a first PERCIST progressive disease (PD) without clinical worsening was observed, treatment was continued and a subsequent FDG-PET (PETinterim2) was performed at 3 months of treatment. Pseudo-progression (PsPD) was defined as a PERCIST response/stability on PETinterim2 after an initial PD. If a second PERCIST PD was assessed on PETinterim2, a homogeneous progression of lesions (termed immune homogeneous progressive-disease: iPDhomogeneous) was distinguished from a heterogeneous evolution (termed immune dissociated-response: iDR). A durable clinical benefit (DCB) of immunotherapy was defined as treatment continuation over a 6-month period. The association between PET evolutive profiles and DCB was assessed. RESULTS: Using PERCIST on PETinterim1, 42% (21/50) of patients showed a response or stable disease, most of them (18/21) reached a DCB. In contrast, 58% (29/50) showed a PD, but more than one-third (11/29) were misclassified as they finally reached a DCB. No standard PETinterim1 criteria could accurately distinguished responding from non-responding patients. Treatment was continued in 19/29 of patients with a first PERCIST PD; the subsequent PETinterim2 demonstrated iPDhomogeneous, iDR and PsPD in 42% (8/19), 26% (5/19), and 32% (6/19), respectively. Whereas no patients with iPDhomogeneous experienced a DCB, all patients with iDR and PsPD reached a clinical benefit to immunotherapy. CONCLUSION: In patients with a first PD on PERCIST and treatment continuation, a subsequent PET identifies more than half of them with iDR and PsPD, both patterns being strongly associated with a clinical benefit of immunotherapy.

Persistent pain in intensive care survivors: a systematic review.

BACKGROUND: According to earlier studies where the main aim has been quality of life, there is growing evidence of increased levels of persistent pain in survivors of critical illness. The cause of admission and several factors during intensive care may have associated risk factors for pain persistence. This systematic review aims to determine the incidence or prevalence of persistent pain after critical illness and to identify risk factors for it. METHODS: Six databases were searched, and eventually nine studies were included in the final systematic process. The validity of observational and cross-sectional studies was analysed using the National Institute of Health 'Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies'. RESULTS: The incidence of persistent pain after intensive care varied from 28% to 77%. Risk factors for persistent pain were acute pain at discharge from ICU, higher thoracic trauma score, surgery, pre-existing pain, organ failure, longer length of ventilator or hospital stay, and sepsis. No difference in incidence between medical and surgical patients was found. CONCLUSIONS: New systematic, observational studies are warranted to identify persistent pain-related factors in intensive care to improve pain management protocols and thereby diminish the risk of persistent pain after ICU stay.

Perception of Beauty in the Visually Blind: A Pilot Observational Study.

BACKGROUND: Blind individuals have demonstrated the ability to detect danger and facial expressions without conscious awareness of visual stimuli. These embodied sensations are believed to be the result of primitive neural networks refined by evolutionary adaptations. We postulate that similar embodied sensations may have evolved to allow blind individuals to perceive beauty. OBJECTIVE: To determine whether the visually blind can detect physical beauty. PATIENTS AND METHODS: This observational study consisted of 8 blind and 10 nonblind test subjects and 6 models that were categorized into predetermined beauty categories. Test subjects were individually asked to rate 6 models on a 1 to 10 numerical beauty scale. This process was repeated in both groups while blindfolded (masked). All groups' mean model beauty scores underwent multivariate and univariate analysis. RESULTS: All groups rated preselected (greater than 8) more beautiful models, higher except for the masked, nonblind group. Intraclass correlation was good in the blind raters with a score of 0.751, whereas poor in the nonblind masked raters with a score of 0.458. CONCLUSION: This is the first pilot study demonstrating with supporting evidence that blind individuals can detect beauty and supports that beauty may rely on primal forms of messaging that are subconsciously appreciated.

Anterior and Posterior Commissuroplasty: Taking Labiaplasty to the Next Level.

As the popularity of female cosmetic genital surgery has grown, so has the number of publications detailing surgical techniques, particularly regarding labiaplasty. As a nascent surgical field, much room remains for finesse and exploration of new techniques to optimize outcomes and patient satisfaction. We present the techniques for anterior and posterior commissuroplasty the senior author (O.J.P.) has developed. Anterior commissuroplasty is efficacious in addressing a number of anatomic variations to achieve the appearance of a single midline cleft, which is commonly requested by patients. Posterior commissuroplasty was developed to address skin excess at the posterior fourchette that may develop as a result of labiaplasty. Either technique may be used in combination with labiaplasty or as a stand-alone procedure. These tools may be a useful addition to the repertoire of a surgeon practicing female genital surgery.

Crizotinib in c-MET- or ROS1-positive NSCLC: results of the AcSé phase II trial.

BACKGROUND: In 2013, the French National Cancer Institute initiated the AcSé program to provide patients with secure access to targeted therapies outside of their marketed approvals. Efficacy and safety was then assessed using a two-stage Simon phase II trial design. When the study design was designed, crizotinib was approved only as monotherapy for adults with anaplastic lymphoma kinase plus non-small-cell lung cancers (NSCLC). PATIENTS AND METHODS: Advanced NSCLC patients with c-MET ≥6 copies, c-MET-mutated, or ROS-1-translocated tumours were enrolled in one of the three cohorts. Patients were treated with crizotinib 250 mg twice daily. Efficacy was assessed using the objective response rate (ORR) after two cycles of crizotinib as primary outcome. Secondary outcomes included disease control rate at four cycles, best ORR, progression-free survival, overall survival, and drug tolerance. RESULTS: From August 2013 to March 2018, 5606 patients had their tumour tested for crizotinib targeted molecular alterations: 252 patients had c-MET ≥6 copies, 74 c-MET-mutation, and 78 ROS-1-translocated tumour. Finally, 25 patients in the c-MET ≥6 copies cohort, 28 in the c-MET-mutation cohort, and 37 in the ROS-1-translocation cohort were treated in the phase II trial. The ORR was 16% in the c-MET ≥6 copies cohort, 10.7% in the mutated, and 47.2% in the ROS-1 cohort. The best ORR during treatment was 32% in the c-MET-≥6 copies cohort, 36% in the c-MET-mutated, and 69.4% in the ROS-1-translocation cohort. Safety data were consistent with that previously reported. CONCLUSIONS: Crizotinib activity in patients with ROS1-translocated tumours was confirmed. In the c-MET-mutation and c-MET ≥6 copies cohorts, despite insufficient ORR after two cycles of crizotinib, there are signs of late response not sufficient to justify the development of crizotinib in this indication. The continued targeting of c-MET with innovative therapies appears justified. CLINICAL TRIAL NUMBER: NCT02034981.

[Pharmacotherapy of chronic neuropathic pain]. / Pharmakologische Therapie chronischer neuropathischer Schmerzen.

Chronic neuropathic pain has a prevalence of 6.9-10% in the general population. The current recommendations for treatment are presented based on a literature search. Neuropathic pain requires the use of co-analgesic, antidepressant, anticonvulsant drugs and topical agents because non-opioid analgesic drugs are usually ineffective. The use of meta-analyses tricyclic antidepressants, selective serotonin-norephinephrine reuptake inhibitors, and calcium channel anticonvulsants are recommended as the drugs of first choice. Under certain conditions chronic neuropathic pain can be treated with opioids. Topical therapeutics are only used to treat peripheral neuropathic pain. At present the use of drugs is independent of the etiology of the pain. Comorbidities, concomitant medication, potential side effects and patients' age have to be considered in treatment planning.

[Chronic hypoxia and cardiovascular risk : Clinical significance of different forms of hypoxia]. / Chronische Hypoxie und kardiovaskuläres Risiko : Klinische Bedeutung verschiedener Hypoxieformen.

It is of fundamental importance to differentiate whether chronic hypoxia occurs intermittently or persistently. While chronic intermittent hypoxia (CIH) is found typically in patients with obstructive sleep apnea (OAS), chronic persistent hypoxia (CPH) is typically diagnosed in patients with chronic lung disease. Cardiovascular risk is markedly increased in patients with CIH compared to patients with CPH. The frequent change between oxygen desaturation and reoxygenation in patients with CIH is associated with increased hypoxic stress, increased systemic inflammation, and enhanced adrenergic activation followed by endothelial dysfunction and increased arteriosclerosis. The pathophysiologic consequences of CPH are less well understood. The relationship between CPH and the development of pulmonary hypertension, pulmonary heart disease as well as polycythemia has been established.

[Long-term changes in multimodal intensive tinnitus therapy : A 5­year follow-up. German version]. / Langzeitveränderung bei multimodaler Tinnitustherapie : Eine 5­Jahres-Katamnese.

BACKGROUND: We present 5­year follow-up data for tinnitus-specific and comorbid depressive symptoms as well as stress-related outcome variables of an intensive multimodal 7­day tinnitus therapy. METHOD: Tinnitus burden (Tinnitus Questionnaire), stress (Perceived Stress Questionnaire), and depressive symptomatology (General Depression Scale) were measured at the 5­year follow-up after a multimodal intensive 7­day intervention. In all, 94 patients participated in the study. RESULTS: All outcome variables showed significant improvement at the end of the 7­day intensive treatment. These effects remained significant after 5 years. CONCLUSION: The results of the present study support the effectiveness of the 7­day multimodal intensive therapy for tinnitus. Posttreatment improvements were related to both tinnitus burden as well as stress and depressive symptoms and were maintained at the 5­year follow-up.

Erratum to: Long-term changes in multimodal intensive tinnitus therapy. A 5-year follow-up.

Erratum to:HNO 2018 66 (Suppl):S34-S38 https://doi.org/10.1007/s00106-017-0463-4 Figure 1 was published incorrectly in the online version of this paper. The correct Figure is reproduced below.

Long-term changes in multimodal intensive tinnitus therapy : A 5­year follow-up.

BACKGROUND: We present 5­year follow-up data for tinnitus-specific and comorbid depressive symptoms as well as stress-related outcome variables of an intensive multimodal 7­day tinnitus therapy. METHOD: Tinnitus burden (Tinnitus Questionnaire), stress (Perceived Stress Questionnaire), and depressive symptomatology (General Depression Scale) were measured at the 5­year follow-up after a multimodal intensive 7­day intervention. In all, 94 patients participated in the study. RESULTS: All outcome variables showed significant improvement at the end of the 7­day intensive treatment. These effects remained significant after 5 years. CONCLUSION: The results of the present study support the effectiveness of the 7­day multimodal intensive therapy for tinnitus. Posttreatment improvements were related to both tinnitus burden as well as stress and depressive symptoms and were maintained at the 5­year follow-up.

Total haemoglobin mass, but not haemoglobin concentration, is associated with preoperative cardiopulmonary exercise testing-derived oxygen-consumption variables.

Background: Cardiopulmonary exercise testing (CPET) measures peak exertional oxygen consumption ( V˙O2peak ) and that at the anaerobic threshold ( V˙O2 at AT, i.e. the point at which anaerobic metabolism contributes substantially to overall metabolism). Lower values are associated with excess postoperative morbidity and mortality. A reduced haemoglobin concentration ([Hb]) results from a reduction in total haemoglobin mass (tHb-mass) or an increase in plasma volume. Thus, tHb-mass might be a more useful measure of oxygen-carrying capacity and might correlate better with CPET-derived fitness measures in preoperative patients than does circulating [Hb]. Methods: Before major elective surgery, CPET was performed, and both tHb-mass (optimized carbon monoxide rebreathing method) and circulating [Hb] were determined. Results: In 42 patients (83% male), [Hb] was unrelated to V˙O2 at AT and V˙O2peak ( r =0.02, P =0.89 and r =0.04, P =0.80, respectively) and explained none of the variance in either measure. In contrast, tHb-mass was related to both ( r =0.661, P <0.0001 and r =0.483, P =0.001 for V˙O2 at AT and V˙O2peak , respectively). The tHb-mass explained 44% of variance in V˙O2 at AT ( P <0.0001) and 23% in V˙O2peak ( P =0.001). Conclusions: In contrast to [Hb], tHb-mass is an important determinant of physical fitness before major elective surgery. Further studies should determine whether low tHb-mass is predictive of poor outcome and whether targeted increases in tHb-mass might thus improve outcome.