Verrucous Carcinoma of the Foot: A Single Canadian Center Experience on Diagnosis, Management, and Outcomes.

INTRODUCTION: Verrucous carcinoma (VC) was first described in 1948 by Dr. Ackerman. It is a low-grade cutaneous squamous carcinoma that usually develops in the oral cavity, the anogenital region, and the plantar surface of the foot. Clinically, there is low suspicion for malignancy given the slow growth of VC lesions and their wart-like appearance. Diagnosis can be difficult because of the benign histological appearance with well-differentiated cells and absence of dysplasia. Surgical excision is the only satisfactory form of treatment for plantar VC; however, this becomes difficult given its benign clinical appearance and the pathologic misinterpretation of the lesion as a benign hyperplasia. While there are case reports and retrospective studies of patients with plantar VC in the literature, we present the largest case series of plantar VC within North America, with recurrence despite negative margins. METHODS: We report on all the plantar VC excised between 2014-2023. We report six cases of VC, their treatment, and their outcomes. RESULTS: Six patients obtained a diagnosis of plantar VC by incisional biopsy. All patients underwent excision of their lesions and had negative margins reported on the final pathology. All patients developed nonhealing wounds at the site of their lesion excision; therefore, biopsies were performed to confirm a recurrence. All patients had a recurrence of VC at the initial site. All patients underwent re-excision of the lesions. Despite negative margins again on final pathology, all patients had a subsequent second recurrence. Ultimately, all patients underwent an amputation as definitive management. Each patient had an average of 3 operations. There were 4 different surgeons and different pathologists reporting their findings. CONCLUSIONS: Our experience with plantar VC suggests that an aggressive approach to surgical management is needed. Furthermore, management is optimized with the combined expertise of an experienced dermatopathologist and surgeon. Despite negative margins and repeated excisions, VC lesions recur and invade local tissues to the extent that only amputation of the involved foot has resulted in cure.

Robotic surgery in gynaecology: Scientific Impact Paper No. 71 (July 2022).

The use of robotic-assisted keyhole surgery in gynaecology has expanded in recent years owing to technical advances. These include 3D viewing leading to improved depth perception, limitation of tremor, potential for greater precision and discrimination of tissues, a shorter learning curve and improved comfort for surgeons compared with conventional keyhole and open abdominal surgery. Robotic-assisted keyhole surgery, compared with conventional keyhole surgery, improves surgical performance without increasing operating time, minimises blood loss and intra- or postoperative complications, while reducing the need to revert to abdominal surgery. Moreover, surgeons using a robot experience fewer skeletomuscular problems of their own in the short and long term than those operating without a robot as an additional tool. This Scientific Impact Paper looks at the use of a robot in different fields of gynaecological surgery. A robot could be considered safe and a more effective surgical tool than conventional keyhole surgery for women who have to undergo complex gynaecology surgery or have associated medical issues such as body-mass index (BMI) at 30 kg/m2 or above or lung problems. The introduction of the use of robots in keyhole surgery has resulted in a decrease in the number of traditional open surgeries and the risk of conversion to open surgery after traditional keyhole surgery; both of which should be considered when examining the cost-benefit of using a robot. Limitations of robotic-assisted surgery remain the associated higher costs. In womb cancer surgery there is good evidence that introducing robotics into the service improves outcomes for women and may reduce costs.

Two-dimensional wavefront characterization of adaptable corrective optics and Kirkpatrick-Baez mirror system using ptychography.

Aberrations introduced during fabrication degrade the performance of X-ray optics and their ability to achieve diffraction limited focusing. Corrective optics can counteract these errors by introducing wavefront perturbations prior to the optic which cancel out the distortions. Here we demonstrate two-dimensional wavefront correction of an aberrated Kirkpatrick-Baez mirror pair using adaptable refractive structures. The resulting two-dimensional wavefront is measured using hard X-ray ptychography to recover the complex probe wavefield with high spatial resolution and model the optical performance under coherent conditions. The optical performance including the beam caustic, focal profile and wavefront error is examined before and after correction with both mirrors found to be diffraction limited after correcting. The results will be applicable to a wide variety of high numerical aperture X-ray optics aiming to achieve diffraction limited focussing using low emittance sources.

Nanoparticle-encapsulated antioxidant improves placental mitochondrial function in a sexually dimorphic manner in a rat model of prenatal hypoxia.

Pregnancy complications associated with prenatal hypoxia lead to increased placental oxidative stress. Previous studies suggest that prenatal hypoxia can reduce mitochondrial respiratory capacity and mitochondrial fusion, which could lead to placental dysfunction and impaired fetal development. We developed a placenta-targeted treatment strategy using a mitochondrial antioxidant, MitoQ, encapsulated into nanoparticles (nMitoQ) to reduce placental oxidative stress and (indirectly) improve fetal outcomes. We hypothesized that, in a rat model of prenatal hypoxia, nMitoQ improves placental mitochondrial function and promotes mitochondrial fusion in both male and female placentae. Pregnant rats were treated with saline or nMitoQ on gestational day (GD) 15 and exposed to normoxia (21% O2 ) or hypoxia (11% O2 ) from GD15-21. On GD21, male and female placental labyrinth zones were collected for mitochondrial respirometry assessments, mitochondrial content, and markers of mitochondrial biogenesis, fusion and fission. Prenatal hypoxia reduced complex IV activity and fusion in male placentae, while nMitoQ improved complex IV activity in hypoxic male placentae. In female placentae, prenatal hypoxia decreased respiration through the S-pathway (complex II) and increased N-pathway (complex I) respiration, while nMitoQ increased fusion in hypoxic female placentae. No changes in mitochondrial content, biogenesis or fission were found. In conclusion, nMitoQ improved placental mitochondrial function in male and female placentae from fetuses exposed to prenatal hypoxia, which may contribute to improved placental function. However, the mechanisms (ie, changes in mitochondrial respiratory capacity and mitochondrial fusion) were distinct between the sexes. Treatment strategies targeted against placental oxidative stress could improve placental mitochondrial function in complicated pregnancies.

Reconstruction of Quadriceps Function Using a Single Functional Gracilis Muscle Transfer With an Adductor Longus Nerve to Femoral Nerve Branch of the Rectus Femoris Nerve Transfer.

BACKGROUND: A femoral nerve injury may result in cutaneous sensory disturbances of the anteromedial thigh and complete paralysis of the quadriceps femoris muscles resulting in an inability to extend the knee. The traditional mainstay of treatment for femoral neuropathy is early physiotherapy, knee support devices, and pain control. Case reports have used the anterior division of the obturator nerve as a donor nerve to innervate the quadriceps femoris muscles; however, a second nerve transfer or nerve grafting is often required for improved outcomes. We suggest a novel technique of combining an innervated, pedicled gracilis transfer with an adductor longus to rectus femoris nerve transfer to restore the strength and stability of the quadriceps muscles. METHODS: This is a case series describing the use of a pedicled gracilis muscle transposed into the rectus femoris position with a concomitant nerve transfer from the adductor longus nerve branch into the rectus femoris nerve branch to restore quadriceps function after iatrogenic injury (hip arthroplasty) and trauma (gunshot wound). RESULTS: With electrodiagnostic confirmation of severe denervation of the quadriceps muscles and no evidence of elicitable motor units, 2 patients (average age, 47 years) underwent a quadriceps muscle reconstruction with a pedicled, innervated gracilis muscle and an adductor longus to recuts femoris nerve transfer. At 1 year follow-up, the patients achieved 4.5/5 British Medical Research Council full knee extension, a stable knee, and the ability to ambulate without an assistive aid. CONCLUSIONS: The required amount of quadriceps strength necessary to maintain quality of life has not been accurately established. In the case of femoral neuropathy, we assumed that a nerve transfer alone and a gracilis muscle transfer alone would not provide enough stability and strength to restore quadriceps function. We believe that the restoration of the quadriceps function after femoral nerve injury can be achieved by combining an innervated, pedicled gracilis transfer with an adductor longus to rectus femoris nerve transfer with low morbidity and no donor defects.

Hard X-ray ptychography for optics characterization using a partially coherent synchrotron source.

Ptychography is a scanning coherent diffraction imaging technique which provides high resolution imaging and complete spatial information of the complex electric field probe and sample transmission function. Its ability to accurately determine the illumination probe has led to its use at modern synchrotrons and free-electron lasers as a wavefront-sensing technique for optics alignment, monitoring and correction. Recent developments in the ptychography reconstruction process now incorporate a modal decomposition of the illuminating probe and relax the restriction of using sources with high spatial coherence. In this article a practical implementation of hard X-ray ptychography from a partially coherent X-ray source with a large number of modes is demonstrated experimentally. A strongly diffracting Siemens star test sample is imaged using the focused beam produced by either a Fresnel zone plate or beryllium compound refractive lens. The recovered probe from each optic is back propagated in order to plot the beam caustic and determine the precise focal size and position. The power distribution of the reconstructed probe modes also allows the quantification of the beams coherence and is compared with the values predicted by a Gaussian-Schell model and the optics exit intensity.

Placenta-targeted treatment in hypoxic dams improves maturation and growth of fetal cardiomyocytes in vitro via the release of placental factors.

NEW FINDINGS: What is the central question of this study? Does treatment of hypoxic dams with a placenta-targeted antioxidant prevent the release of placenta-derived factors that impair maturation or growth of fetal cardiomyocytes in vitro? What is the main finding and its importance? Factors released from hypoxic placentae impaired fetal cardiomyocyte maturation (induced terminal differentiation) and growth (increased cell size) in vitro, which was prevented by maternal treatment with a placenta-targeted antioxidant (nMitoQ). Moreover, there were no sex differences in the effects of placental factors on fetal cardiomyocyte maturation and growth. Overall, our data suggest that treatment targeted against placental oxidative stress could prevent fetal programming of cardiac diseases via the release of placental factors. ABSTRACT: Pregnancy complications associated with placental oxidative stress may impair fetal organ development through the release of placenta-derived factors into the fetal circulation. We assessed the effect of factors secreted from placentae previously exposed to prenatal hypoxia on fetal cardiomyocyte development and developed a treatment strategy that targets placental oxidative stress by encapsulating the antioxidant MitoQ into nanoparticles (nMitoQ). We used a rat model of prenatal hypoxia (gestational day (GD) 15-21), which was treated with saline or nMitoQ on GD15. On GD21, placentae were harvested, placed in culture, and conditioned medium (containing placenta-derived factors) was collected after 24 h. This conditioned medium was then added to cultured cardiomyocytes from control dam fetuses. Conditioned medium from prenatally hypoxic placentae increased the percentage of binucleated cardiomyocytes (marker of terminal differentiation) and the size of mononucleated and binucleated cardiomyocytes (sign of hypertrophy), effects that were prevented by nMitoQ treatment. Our data suggest that factors derived from placentae previously exposed to prenatal hypoxia lead to abnormal fetal cardiomyocyte development, and show that treatment against placental oxidative stress may prevent fetal programming of cardiac disease.

Critical speed and finite distance capacity: norms for athletic and non-athletic groups.

PURPOSE: Two parameters in particular span both health and performance; critical speed (CS) and finite distance capacity (D'). The purpose of the present study was to: (1) classify performance norms, (2) distinguish athletic from non-athletic individuals using the 3-min all-out test (3MT) for running, and (3) introduce a deterministic model highlighting the relationship between variables of the 3MT. METHODS: Athletic (n = 43) and non-athletic (n = 25) individuals participated in the study. All participants completed a treadmill graded exercise test (GXT) with verification bout and a 3MT on an outdoor sprinting track. RESULTS: Meaningful differences between non-athletic and athletic individuals (denoted by mean difference scores, p value and Cohen's d with 95% confidence intervals) were evident for CS (- 0.74 m s-1, p < 0.001, d = - 1.41 [1.97, - 0.87]), exponential growth time constant ([Formula: see text]; 2.75 s, p < 0.001, d = - 1.29 [- 1.45, - 0.42]), time to maximal speed ([Formula: see text]; - 2.80 s, p < 0.001, d = - 0.98 [- 1.51, - 0.47]), maximal speed ([Formula: see text]; - 1.36 m s-1, p < 0.001, d = - 1.56 [- 2.13, - 1.01]), gas exchange threshold (GET; - 5.62 ml kg-1 min-1, p < 0.001, d = - 0.97 [- 1.50, - 0.45]), distance covered in the first minute (1st min; - 81.69 m, p < 0.001, d = - 1.91 [- 2.52, - 1.33]), distance covered in the second minute (2nd min; - 52.02 m, p < 0.001, d = - 1.71 [- 2.30, - 1.15]) and maximal distance (- 153.78 m, p < 0.001, d = - 1.27 [- 1.82, - 0.74]). The correlation coefficient between key physiological and performance variables are shown in the form of a deterministic model created from the data derived from the 3MT. CONCLUSIONS: Coaches and clinicians may benefit from the use of normative data to potentially identify exceptional or irregular occurrences in 3MT performances.

Computed Tomographic Angiography Used for Localization of the Cutaneous Perforators and Selection of Anterolateral Thigh Flap "Bail-Out" Branches.

BACKGROUND: The purpose of this study was to evaluate the territory supplied by the lateral circumflex femoral artery for the consistency of a proximal perforator that could be used as an alternative pedicle for the anterolateral thigh flap if a tedious intramuscular course is encountered during elevation of the perforator used to develop the initial surgical plan. It is hypothesized that a consistent "bail-out" perforator supplying the proximal thigh would facilitate a simpler anterolateral thigh flap harvest, with minimal modification to flap design. METHODS: Computed tomographic images of 9 fresh cadavers were imported using Materialize's Interactive Medical Imaging Control System software to create surface-rendered 3-dimensional reconstructions of 15 lower limbs. Perforators emerging proximally and laterally to a 3-cm radius circle drawn at the midpoint of the anterior superior iliac spine and superolateral patella were considered potential bail-out perforators and evaluated for their number emerging diameter, length, course, and location relative to the anterior superior iliac spine. RESULTS: An average of 2.9 ± 1.8 perforators per limb were identified. Mean pedicle length was 111 ± 20 mm, measured from the origin in the lateral circumflex femoral artery to where the perforators emerged through the deep fascia directly overlying the thigh muscles. Average diameter at origin in the lateral circumflex femoral artery was 2.8 ± 0.8 mm, and that at emergence through the deep fascia was 1.1 ± 0.3 mm. Vessel course was predominantly musculocutaneous (90%). CONCLUSIONS: A significant bail-out perforator routinely supplies the proximal anterolateral thigh and may be used as an alternative vascular pedicle for an anterolateral thigh flap if a tedious intramuscular course is encountered during elevation of a perforator identified within the conventional landmarks (3-cm radius circle at the midpoint of the anterior superior iliac spine and superolateral patella).

Separation of type and grade in cervical tumours using non-mono-exponential models of diffusion-weighted MRI.

OBJECTIVES: Assessment of empirical diffusion-weighted MRI (DW-MRI) models in cervical tumours to investigate whether fitted parameters distinguish between types and grades of tumours. METHODS: Forty-two patients (24 squamous cell carcinomas, 14 well/moderately differentiated, 10 poorly differentiated; 15 adenocarcinomas, 13 well/moderately differentiated, two poorly differentiated; three rare types) were imaged at 3 T using nine b-values (0 to 800 s mm-2). Mono-exponential, stretched exponential, kurtosis, statistical, and bi-exponential models were fitted. Model preference was assessed using Bayesian Information Criterion analysis. Differences in fitted parameters between tumour types/grades and correlation between fitted parameters were assessed using two-way analysis of variance and Pearson's linear correlation coefficient, respectively. RESULTS: Non-mono-exponential models were preferred by 83 % of tumours with bi-exponential and stretched exponential models preferred by the largest numbers of tumours. Apparent diffusion coefficient (ADC) and diffusion coefficients from non-mono-exponential models were significantly lower in poorly differentiated tumours than well/moderately differentiated tumours. α (stretched exponential), K (kurtosis), f and D* (bi-exponential) were significantly different between tumour types. Strong correlation was observed between ADC and diffusion coefficients from other models. CONCLUSIONS: Non-mono-exponential models were preferred to the mono-exponential model in DW-MRI data from cervical tumours. Parameters of non-mono-exponential models showed significant differences between types and grades of tumours. KEY POINTS: • Non-mono-exponential DW-MRI models are preferred in the majority of cervical tumours. • Poorly differentiated cervical tumours exhibit lower diffusion coefficients than well/moderately differentiated tumours. • Non-mono-exponential model parameters α, K, f, and D* differ between tumour types. • Micro-structural features are likely to affect parameters in non-mono-exponential models differently.

Comparison of optimised endovaginal vs external array coil T2-weighted and diffusion-weighted imaging techniques for detecting suspected early stage (IA/IB1) uterine cervical cancer.

OBJECTIVE: To compare sensitivity and specificity of endovaginal versus external-array coil T2-W and T2-W + DWI for detecting and staging small cervical tumours. METHODS: Optimised endovaginal and external array coil MRI at 3.0-T was done prospectively in 48 consecutive patients with stage Ia/Ib1 cervical cancer. Sensitivity/specificity for detecting tumour and parametrial extension against histopathology for a reading radiologist were determined on coronal T2-W and T2W + DW images. An independent radiologist also scored T2-W images without and with addition of DWI for the external-array and endovaginal coils on separate occasions >2 weeks apart. Cohen's kappa assessed inter- and intra-observer agreement. RESULTS: Median tumour volume in 19/38 cases positive on subsequent histology was 1.75 cm(3). Sensitivity, specificity, PPV, NPV were: reading radiologist 91.3 %, 89.5 %, 91.3 %, 89.5 %, respectively; independent radiologist T2-W 82.6 %, 73.7 %, 79.1 %, 77.8 % for endovaginal, 73.9 %, 89.5 %, 89.5 %, 73.9 % for external-array coil. Adding DWI improved sensitivity and specificity of endovaginal imaging (78.2 %, 89.5 %); adding DWI to external-array imaging improved specificity (94.7 %) but reduced sensitivity (66.7 %). Inter- and intra-observer agreement on T2-W + DWI was good (kappa = 0.67 and 0.62, respectively). CONCLUSION: Endovaginal coil T2-W MRI is more sensitive than external-array coil for detecting tumours <2 cm(3); adding DWI improves specificity of endovaginal imaging but reduces sensitivity of external-array imaging. KEY POINTS: • Endovaginal more accurate than external-array T2-W MRI for detecting small cervical cancers. • Addition of DWI improves sensitivity and specificity of endovaginal T2-W imaging. • Addition of DWI substantially reduces sensitivity of external-array T2-W imaging.

Outcome of Appendicectomies at Surgery for Mucinous Ovarian Neoplasms: Report From A UK Center and Review of Literature.

OBJECTIVE: This study aimed to determine the frequency of malignant pathology in a macroscopically normal appendix during surgery for a borderline or malignant mucinous ovarian tumor (MOT). METHODS: Women with borderline and malignant MOT were identified from the pathology database from 2000 to 2014. Women who had a benign MOT and had an appendicectomy were excluded from the study. Data were collected from the electronic patient record and case notes. RESULTS: Of 310 women identified with MOT, 203 patients with benign MOT were excluded. Of the remaining 107 patients, 15 patients with previous appendicectomy were also excluded. The study population consisted of 92 patients. There were 57 (62%) patients with borderline MOT and 35 (38%) patients with malignant MOT. In the borderline subgroup, 40/57 (70%) patients had appendicectomy of whom 8 (20%) had macroscopically abnormal appendices. One patient had pseudomyxoma peritonei secondarily involving the appendix and 7 patients had a histologically normal appendix. Normal histology was found in all macroscopically normal appendices. In the malignant subgroup, 29/35 (83%) patients had an appendicectomy. There were 8 (27.5%) macroscopically abnormal appendices with a malignant pathology in 7 (87.5%) patients and 1 patient had a resolving appendicitis. There were 21 macroscopically normal appendices of which, serrated adenoma was found in 1 (4.8%) patient, whereas the remaining 20 (95.2%) patients had normal histology. CONCLUSIONS: In MOT, an abnormal appearing appendix should be excised. If the appendix is grossly normal, our data do not support performing an appendicectomy as part of a surgical staging procedure.

Excision With Interpositional Nerve Grafting: An Alternative Technique for the Treatment of Morton Neuroma.

INTRODUCTION: "Morton neuroma" is a common cause of forefoot pain with numbness frequently occurring in the distribution of the third common digital nerve. After the failure of nonoperative measures, decompression with excision of the neuroma is common practice. Residual numbness and recurrent pain has been reported as a consequence of this treatment option. This study describes excision of the neuroma with interpositional nerve grafting as a treatment option for Morton neuroma. This proposed technique has the benefit of reducing pain, reducing recurrent secondary neuromas and restoring postexcision sensory deficits. METHODS: A retrospective chart review of patients who underwent elective primary excision of a Morton neuroma with interpositional nerve grafting was undertaken. Patient demographics, surgical technique, and clinical outcomes, such as pain, neuroma recurrence, 2-point discrimination, numbness, and weight-bearing status at minimum of 1 year postoperation, are reported. RESULTS: Eight patients (9 neuromas) underwent excision of the Morton neuroma with interpositional nerve grafting after failing nonoperative measures. At final follow-up, all patients had improvement of pain and there were no neuroma recurrences. Sensation to the grafted hemi-toe returned in all but 1 case. All patients returned to full weight-bearing status. Although no major complications were reported, wound dehiscence secondary to a hematoma occurred in 1 case. CONCLUSIONS: Excision and interpositional nerve grafting is an effective treatment for Morton neuroma as it alleviates pain, numbness and restores sensation with minimal morbidity and complications.

Social-economical decision making in current and remitted major depression.

BACKGROUND: Prosocial emotions related to self-blame are important in guiding human altruistic decisions. These emotions are elevated in major depressive disorder (MDD), such that MDD has been associated with guilt-driven pathological hyper-altruism. However, the impact of such emotional impairments in MDD on different types of social decision-making is unknown. METHOD: In order to address this issue, we investigated different kinds of altruistic behaviour (interpersonal cooperation and fund allocation, altruistic punishment and charitable donation) in 33 healthy subjects, 35 patients in full remission (unmedicated) and 24 currently depressed patients (11 on medication) using behavioural-economical paradigms. RESULTS: We show a significant main effect of clinical status on altruistic decisions (p = 0.04) and a significant interaction between clinical status and type of altruistic decisions (p = 0.03). More specifically, symptomatic patients defected significantly more in the Prisoner's Dilemma game (p < 0.05) and made significantly lower charitable donations, whether or not these incurred a personal cost (p < 0.05 and p < 0.01, respectively). Currently depressed patients also reported significantly higher guilt elicited by receiving unfair financial offers in the Ultimatum Game (p < 0.05). CONCLUSIONS: Currently depressed individuals were less altruistic in both a charitable donation and an interpersonal cooperation task. Taken together, our results challenge the guilt-driven pathological hyper-altruism hypothesis in depression. There were also differences in both current and remitted patients in the relationship between altruistic behaviour and pathological self-blaming, suggesting an important role for these emotions in moral and social decision-making abnormalities in depression.

Temporal discounting in major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is associated with abnormalities in financial reward processing. Previous research suggests that patients with MDD show reduced sensitivity to frequency of financial rewards. However, there is a lack of conclusive evidence from studies investigating the evaluation of financial rewards over time, an important aspect of reward processing that influences the way people plan long-term investments. Beck's cognitive model posits that patients with MDD hold a negative view of the future that may influence the amount of resources patients are willing to invest into their future selves. METHOD: We administered a delay discounting task to 82 participants: 29 healthy controls, 29 unmedicated participants with fully remitted MDD (rMDD) and 24 participants with current MDD (11 on medication). RESULTS: Patients with current MDD, relative to remitted patients and healthy subjects, discounted large-sized future rewards at a significantly higher rate and were insensitive to changes in reward size from medium to large. There was a main effect of clinical group on discounting rates for large-sized rewards, and discounting rates for large-sized rewards correlated with severity of depressive symptoms, particularly hopelessness. CONCLUSIONS: Higher discounting of delayed rewards in MDD seems to be state dependent and may be a reflection of depressive symptoms, specifically hopelessness. Discounting distant rewards at a higher rate means that patients are more likely to choose immediate financial options. Such impairments related to long-term investment planning may be important for understanding value-based decision making in MDD, and contribute to ongoing functional impairment.

State-dependent changes in hippocampal grey matter in depression.

Reduced hippocampal volume has been reported in depression and may be involved in the aetiology of depressive symptoms and vulnerability to depressive relapse. Neuroplasticity following antidepressant drug treatment in the hippocampus has been demonstrated in animal models but adaptive changes after such treatment have not been shown in humans. In this study, we determined whether grey matter loss in the hippocampus in depression (1) is present in medication-free depressed (2) changes in response to antidepressant treatment and (3) is present as a stable trait in medication-free remitted patients. Sixty-four medication-free unipolar depressed patients: 39 currently depressed and 25 in remission, and 66 healthy controls (HC) underwent structural magnetic resonance imaging in a cross-sectional and longitudinal design. Thirty-two currently depressed participants were then treated with the antidepressant citalopram for 8 weeks. Adherence to treatment was evaluated by measuring plasma citalopram concentration. We measured regional variation in grey matter concentration by using voxel-based morphometry-Diffeomorphic Anatomical Registration Through Exponentiated Lie algebra. Patients with current depression had bilaterally reduced grey matter in the hippocampus compared with HC and untreated patients in stable remission with the latter groups not differing. An increase in grey matter was observed in the hippocampus following treatment with citalopram in currently depressed patients. Grey matter reduction in the hippocampus appears specific to the depressed state and is a potential biomarker for a depressive episode.

Preoperative imaging in patients undergoing trachelectomy for cervical cancer: validation of a combined T2- and diffusion-weighted endovaginal MRI technique at 3.0 T.

AIM: The aim of this study is to validate high-resolution endovaginal T2- and diffusion-weighted MRI measurements (tumour size, volume and length of uninvolved cervical canal) against histology in patients undergoing trachelectomy. PATIENTS/INTERVENTIONS: 55 consecutive patients 25-44 years with cervical cancer being considered for trachelectomy were prospectively assessed with endovaginal T2-W and diffusion-weighted MRI. Two independent observers blinded to histology recorded maximum tumour dimension, volume and distance from the superior aspect of the tumour to the internal os. Following trachelectomy, pathologist-outlined tumour sections were photographed with a set scale and similar measurements were recorded. RESULTS: Fifteen of 45 patients subsequently treated with fertility-sparing surgery had residual tumour (median histological volume: 0.28 cm(3), IQR=0.14-1.06 cm(3)). Sensitivity, specificity, positive and negative predictive values for detecting tumour: Observer 1: 86.7%, 80.0%, 68.4%, and 92.3%, respectively; Observer 2: 86.7%, 90.0%, 81.0%, and 93.1%, respectively. Size and volume correlated between observers (r=0.96, 0.84, respectively, p<0.0001). Size correlated between each observer and histology (observer 1 r=0.91, p<0.0001; observer 2 r=0.93, p<0.0001), volume did not (observer 1: r=0.08, p=0.6; observer 2: r=0.21, p=0.16); however, differences between observer measurements and histology were not significant (size p=0.09, volume p=0.15). Differences between MRI and histology estimates of endocervical canal length were not significant (p=0.1 both observers). CONCLUSION: In subcentimetre cervical cancers, endovaginal MRI correlates with pathology and is invaluable in assessing patients for fertility-sparing surgery.

Fat Necrosis in Single Perforator Deep Inferior Epigastric Artery and Superficial Epigastric Artery Perforator Free Flaps: A Prospective Randomized Study.

Background: The deep inferior epigastric perforator (DIEP) flap is the standard of care in autologous breast reconstruction. The superficial inferior epigastric artery perforator flap (SIEA) is an alternative reconstructive option, with the compromise of less donor-site morbidity but variable perfusion to subscarpal fat zones. Fat necrosis is a known complication from marginal perfusion variability. Volumetric analysis of fat necrosis has not been performed between the two reconstructive options, nor has the amount of flap necrosis following radiation. Our objective was to compare rates and volume of fat necrosis between single-perforator DIEP and SIEA flap techniques. Methods: A single-center, blinded, prospective cohort study of patients randomized between SIEA and DIEP breast reconstruction was conducted over 2 years (June 2011-July 2013). Inclusion criteria were women undergoing immediate reconstruction following mastectomy. Randomization protocols were strictly followed. Fat necrosis volumetric analysis was determined by an ultrasound-trained attending surgeon at 12 months postoperatively. Patient demographics and adjuvant/neoadjuvant cancer treatment were analyzed. Statistical analyses included Mann-Whitney U tests, chi square, and/or Fisher exact tests. P values of 0.05 or less were considered significant. Results: Fat necrosis was detected in 11 of 46 flaps (23.9%), with a median area of 17.9 cm2. There was no significant difference in prevalence of fat necrosis between the two flap types (P = 0.19). Postoperative radiation did not increase the prevalence (P = 0.30) or extent (P = 0.92) of fat necrosis. Conclusion: Single-perforator DIEP and SIEA flaps have comparable rates of fat necrosis. Postoperative radiation did not result in increased prevalence or extent of fat necrosis.

Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure.

Approximately 3.3 billion people live with the threat of Plasmodium vivax malaria. Infection can result in liver-localized hypnozoites, which when reactivated cause relapsing malaria. This work demonstrates that an enzyme-cleavable polymeric prodrug of tafenoquine addresses key requirements for a mass administration, eradication campaign: excellent subcutaneous bioavailability, complete parasite control after a single dose, improved therapeutic window compared to the parent oral drug, and low cost of goods sold (COGS) at less than $1.50 per dose. Liver targeting and subcutaneous dosing resulted in improved liver:plasma exposure profiles, with increased efficacy and reduced glucose 6-phosphate dehydrogenase-dependent hemotoxicity in validated preclinical models. A COGS and manufacturability analysis demonstrated global scalability, affordability, and the ability to redesign this fully synthetic polymeric prodrug specifically to increase global equity and access. Together, this polymer prodrug platform is a candidate for evaluation in human patients and shows potential for P. vivax eradication campaigns.