Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer.

BACKGROUND: Immunotherapy has transformed the endometrial cancer treatment landscape, particularly for those exhibiting mismatch repair deficiency [MMRd/microsatellite instability-hypermutated (MSI-H)]. A growing body of evidence supports the integration of immunotherapy with chemotherapy as a first-line treatment strategy. Recently, findings from ongoing trials such as RUBY (NCT03981796), NRG-GY018 (NCT03914612), AtTEnd (NCT03603184), and DUO-E (NCT04269200) have been disclosed. MATERIALS AND METHODS: This paper constitutes a review and meta-analysis of phase III trials investigating the role of immunotherapy in the first-line setting for advanced or recurrent endometrial cancer. RESULTS: The pooled data from 2320 patients across these trials substantiate the adoption of chemotherapy alongside immunotherapy, revealing a significant improvement in progression-free survival compared to chemotherapy alone [hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.62-0.79] across all patient groups. Progression-free survival benefits are more pronounced in MMRd/MSI-H tumors (n = 563; HR 0.33, 95% CI 0.23-0.43). This benefit, albeit less robust, persists in the MMR-proficient/microsatellite stable group (n = 1757; HR 0.74, 95% CI 0.60-0.91). Pooled data further indicate that chemotherapy plus immunotherapy enhances overall survival compared to chemotherapy alone in all patients (HR 0.75, 95% CI 0.63-0.89). However, overall survival data maturity remains low. CONCLUSIONS: The incorporation of immunotherapy into the initial treatment for advanced and metastatic endometrial cancer brings about a substantial improvement in oncologic outcomes, especially within the MMRd/MSI-H subset. This specific subgroup is currently a focal point of investigation for evaluating the potential of chemotherapy-free regimens. Ongoing exploratory analyses aim to identify non-responding patients eligible for inclusion in clinical trials.

Stable, narrow-linewidth laser system with a broad frequency tunability and a fast switching time.

For a Rydberg atom-based sensor to change its sensing frequency, the wavelength of the Rydberg state excitation laser must be altered. The wavelength shifts required can be on the order of 10 nm. A fast-tunable narrow-linewidth laser with broadband tuning capability is required. Here, we present a demonstration of a laser system that can rapidly switch a coupling laser as much as 8 nm in less than 50 µs. The laser system comprises a frequency-stabilized continuous wave laser and an electro-optic frequency comb. A filter enables selection of individual comb lines. A high-speed electro-optic modulator is used to tune the selected comb line to a specific frequency, i.e., an atomic transition. Through Rydberg atom-based sensing experiments, we demonstrate frequency hopping between two Rydberg states and a fast switching time of 400 µs, which we show can be reduced to ∼50 µs with a ping-pong scheme. If updating the RF frequency is not required during frequency hopping, a 200 ns switching time can be achieved. These results showcase the potential of the laser system for advanced Rydberg atom-based radio frequency sensing applications, like communications and radar.

Computer-Generated R.E.N.A.L. Nephrometry Scores Yield Comparable Predictive Results to Those of Human-Expert Scores in Predicting Oncologic and Perioperative Outcomes.

PURPOSE: We sought to automate R.E.N.A.L. (for radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry scoring of preoperative computerized tomography scans and create an artificial intelligence-generated score (AI-score). Subsequently, we aimed to evaluate its ability to predict meaningful oncologic and perioperative outcomes as compared to expert human-generated nephrometry scores (H-scores). MATERIALS AND METHODS: A total of 300 patients with preoperative computerized tomography were identified from a cohort of 544 consecutive patients undergoing surgical extirpation for suspected renal cancer at a single institution. A deep neural network approach was used to automatically segment kidneys and tumors, and geometric algorithms were developed to estimate components of R.E.N.A.L. nephrometry score. Tumors were independently scored by medical personnel blinded to AI-scores. AI- and H-score agreement was assessed using Lin's concordance correlation and their predictive abilities for both oncologic and perioperative outcomes were assessed using areas under the curve. RESULTS: Median age was 60 years (IQE 51-68), and 40% were female. Median tumor size was 4.2 cm and 91.3% had malignant tumors, including 27%, 37% and 24% with high stage, grade and necrosis, respectively. There was significant agreement between H-scores and AI-scores (Lin's ⍴=0.59). Both AI- and H-scores similarly predicted meaningful oncologic outcomes (p <0.001) including presence of malignancy, necrosis, and high-grade and -stage disease (p <0.003). They also predicted surgical approach (p <0.004) and specific perioperative outcomes (p <0.05). CONCLUSIONS: Fully automated AI-generated R.E.N.A.L. scores are comparable to human-generated R.E.N.A.L. scores and predict a wide variety of meaningful patient-centered outcomes. This unambiguous artificial intelligence-based scoring is intended to facilitate wider adoption of the R.E.N.A.L. score.

A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium.

OBJECTIVE: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. PATIENTS & METHODS: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. RESULTS: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. CONCLUSIONS: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.

The association between nocturia, hormonal symptoms and bladder parameters in women: an observational study.

OBJECTIVE: Postmenopausal nocturia is poorly understood. This study aimed to identify hormonal and lifestyle factors associated with nocturia and to understand the relative contribution of altered urine production and bladder storage dysfunction in women. DESIGN, SETTING, POPULATION AND METHODS: Women ≥40 years presenting to public continence services were enrolled in a cross-sectional study. A total of 153 participants completed a hormone status questionnaire, a validated nocturia causality screening tool and a 3-day bladder diary. Descriptive statistics and logistic regression models for nocturia severity and bladder diary parameters were computed. RESULTS: Overall, 91.5% reported nocturia, 55% ≥2 /night. There was a difference of 167.5 ml (P < 0.001) in nocturnal urine volume between women with nocturia ≥2 (median 736 ml) versus less often (517 ml). Significant predictors of self-reported disruptive nocturia were age (odds ratio [OR] 1.04, 95% CI 1.002-1.073) and vitamin D supplementation (OR 2.33, 95% CI 1.11-4.91). Nocturnal polyuria was significantly more common with nocturia ≥2 compared with less frequent nocturia (P < 0.002). Exercise for 150 minutes a week was protective for nocturnal polyuria (OR 0.22, P = 0.001). Nocturia index >1.3 was significantly predicted by age (OR 1.07, P < 0.001), regular exercise (OR 0.41, P = 0.036), day flushes (OR 4.00, P = 0.013) and use of vitamin D (OR 2.34, P = 0.043). Maximum voided volumes were significantly lower with nocturia ≥2 versus less often (night: 268 ml versus 350 ml; day: 200 ml versus 290 ml). CONCLUSIONS: Bothersome nocturia in postmenopausal women is associated with changes to both nocturnal diuresis and bladder storage. Regular physical activity, prolapse reduction and oestrogen replacement may be adjunctive in managing bothersome nocturia in women.

Covid-19, Child & Adolescent Mental Health Services (CAMHS) and Crises.

Despite low rates of Covid-19 infection and mortality, children and adolescents have experienced disproportionate restrictions on their personal, social and academic life. Among youth in Ireland, reports of increased attendances by primary care counselling services have been mirrored by increased presentations to emergency departments and specialist mental health services, most notably self-harm and eating disorders. Following an immediate post lock down reduction, emergency department presentations by children for acute mental health care and referrals to child and adolescent mental health services (CAMHS) showed a sustained increase throughout 2020. Urgent action is needed to invest in CAMHS post pandemic to prevent any further increase in psychiatric illness among youth. We all share this collective responsibility to insist of government commitment to our youth.

Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I.

BACKGROUND: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. RESULTS: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. CONCLUSIONS: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

The Archean origin of oxygenic photosynthesis and extant cyanobacterial lineages.

The record of the coevolution of oxygenic phototrophs and the environment is preserved in three forms: genomes of modern organisms, diverse geochemical signals of surface oxidation and diagnostic Proterozoic microfossils. When calibrated by fossils, genomic data form the basis of molecular clock analyses. However, different interpretations of the geochemical record, fossil calibrations and evolutionary models produce a wide range of age estimates that are often conflicting. Here, we show that multiple interpretations of the cyanobacterial fossil record are consistent with an Archean origin of crown-group Cyanobacteria. We further show that incorporating relative dating information from horizontal gene transfers greatly improves the precision of these age estimates, by both providing a novel empirical criterion for selecting evolutionary models, and increasing the stringency of sampling of posterior age estimates. Independent of any geochemical evidence or hypotheses, these results support oxygenic photosynthesis evolving at least several hundred million years before the Great Oxygenation Event (GOE), a rapid diversification of major cyanobacterial lineages around the time of the GOE, and a post-Cryogenian origin of extant marine picocyanobacterial diversity.

Loss of the laminin subunit alpha-3 induces cell invasion and macrophage infiltration in cutaneous squamous cell carcinoma.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is a common cancer that invades the dermis through the basement membrane. The role of the basement membrane in poorly differentiated cSCC is not well understood. OBJECTIVES: To study the effect that loss of the laminin subunit alpha-3 (α3) chain from the tumour microenvironment has on tumour invasion and inflammatory cell recruitment. METHODS: We examined the role of the basement membrane proteins laminin subunits α3, ß3 and γ2 in SCC invasion and inflammatory cell recruitment using immunohistochemistry, short hairpin RNA knockdown, RNA-Seq, mouse xenograft models and patient tumour samples. RESULTS: Analysis of SCC tumours and cell lines using antibodies specific to laminin chains α3, ß3 and γ2 identified a link between poorly differentiated SCC and reduced expression of laminin α3 but not the other laminin subunits investigated. Knockdown of laminin α3 increased tumour invasion both in vitro and in vivo. Western blot and immunohistochemical staining identified increased phosphorylated myosin light chain with loss of laminin α3. Inhibition of ROCK (rho-associated protein kinase) but not Rac1 significantly reduced the invasive potential of laminin α3 knockdown cells. Knockdown of laminin subunits α3 and γ2 increased monocyte recruitment to the tumour microenvironment. However, only the loss of laminin α3 correlated with increased tumour-associated macrophages both in xenografted tumours and in patient tumour samples. CONCLUSIONS: These data provide evidence that loss of the laminin α3 chain in cSCC has an effect on both the epithelial and immune components of cSCC, resulting in an aggressive tumour microenvironment.

A phase Ib/II and pharmacokinetic study of EP0057 (formerly CRLX101) in combination with weekly paclitaxel in patients with recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: EP0057 (formerly CRLX101) is an investigational nanoparticle-drug conjugate (NDC) of a cyclodextrin-based polymer backbone plus camptothecin, a topoisomerase-1 inhibitor. Prior studies showed efficacy in recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer (EOC). METHODS: This phase Ib/2 trial assessed safety and efficacy of EP0057 Q2W plus weekly paclitaxel in patients with EOC. The recommended phase 2 dose (RP2D) was identified using a 3+3 design. The single-arm phase 2 assessed overall response (ORR) per RECIST 1.1 in patients previously treated with bevacizumab. Secondary objectives included progression free survival (PFS) and duration of response. RESULTS: The RP2D was established as 15 mg/m2 EP0057 Q2W plus 80 mg/m2 paclitaxel administered 3 weeks on/1 week off. Nine patients enrolled on phase 1b, with no DLTs; 21 additional patients enrolled on phase 2. All completed >1 cycle. Median age was 62 (44-76) years, 57% ≥3 prior therapies. For the primary analysis, 6/19 patients with prior bevacizumab had confirmed responses (ORR=31.6% (95% CI: 15.4% to 54.0%)) including one complete response (CR). Median PFS was 5.4 months. Most common grade 3/4 adverse events attributed to treatment were decreased neutrophil count (13, 43%) and anemia (3, 10%). CONCLUSIONS: Although the observed ORR was not statistically better than the historical control rate, EP0057 remains an interesting option for treatment of recurrent EOC. EP0057 exhibits high plasma drug retention, slow clearance, and controlled slow release of CPT from the polymer when administered alone and with paclitaxel. (NCT02389985) 242 words.

The forefront of ovarian cancer therapy: update on PARP inhibitors.

BACKGROUND: In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the treatment algorithm. DESIGN: We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-comer and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need. RESULTS: Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety. CONCLUSIONS: PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority.

A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemcitabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE: Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC. METHODS: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with or without paz 800 mg QD, stratified by platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. RESULTS: 148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p < 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p < 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%). CONCLUSIONS: The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab.

Rapid polarization mapping in ferroelectrics using Fourier masking.

Ferroelectric materials, and more specifically ferroelectric domain walls (DWs) have become an area of intense research in recent years. Novel physical phenomena have been discovered at these nanoscale topological polarization discontinuities by mapping out the polarization in each atomic unit cell around the DW in a scanning transmission electron microscope (STEM). However, identifying these features requires an understanding of the polarization in the overall domain structure of the TEM sample, which is often a time-consuming process. Here, a fast method of polarization mapping in the TEM is presented, which can be applied to a range of ferroelectric materials. Due to the coupling of polarization to spontaneous strain, we can isolate different strain states and demonstrate the fast mapping of the domain structure in ferroelectric lead titanate (PTO). The method only requires a high-resolution TEM or STEM image and is less sensitive to zone axis or local strain effects, which may affect other techniques. Thus, it is easily applicable to in-situ experiments. The complimentary benefits of Fourier masking with more advanced mapping strategies and its application to other materials are discussed. These results imply that Fourier masked polarization mapping will be a useful tool for electron microscopists in streamlining their analysis of ferroelectric TEM samples. LAY DESCRIPTION: This paper addresses a problem that often occurs when looking at a ferroelectric material in the Transmission Electron Microscope (TEM). Ferroelectric samples are interesting because they form tiny areas inside themselves with arrow of charge in each one. The thinner the sample, the smaller these regions, called "domains" become. These arrows of charge point in different directions in each domain of the sample. The boundary where these domains meet have interesting properties to study in a TEM but it's important to figure out which way the arrows point in the domains around the boundary. What causes the arrows in the different domains is tiny shifts of different atoms in unit cell away from their neutral position, usually because they're being squeezed by pressure from the domains nearby. The problem is that these tiny atoms moving are difficult to measure and see where the charged arrow is pointing, often it's hard to know how many different domains are even in the sample and where they begin. This paper discusses a method called "Fourier masking" to quickly see what's going on in the overall TEM sample, where the domains are and roughly where the arrows point. It does this by looking at the spacings of the atoms from a magnification where you can just about see the lines of atoms. In lead titanate the unit cell is a rectangle and the arrow always points in line with the long side of the rectangle. The Fourier masking lets you see which direction the long side of the rectangular unit cell is pointing in different parts of your TEM image. The big advantage is that it takes about two minutes to do and uses software that almost every TEM already has. That lets the TEM user quickly know where the domains are in their TEM samples and roughly which way the arrows of charge are pointing. Then they can choose the most interesting features focus on for higher resolution analysis.

Healthcare utilization and monetary costs associated with agitation in UK care home residents with advanced dementia: a prospective cohort study.

OBJECTIVE: Nearly half of care home residents with advanced dementia have clinically significant agitation. Little is known about costs associated with these symptoms toward the end of life. We calculated monetary costs associated with agitation from UK National Health Service, personal social services, and societal perspectives. DESIGN: Prospective cohort study. SETTING: Thirteen nursing homes in London and the southeast of England. PARTICIPANTS: Seventy-nine people with advanced dementia (Functional Assessment Staging Tool grade 6e and above) residing in nursing homes, and thirty-five of their informal carers. MEASUREMENTS: Data collected at study entry and monthly for up to 9 months, extrapolated for expression per annum. Agitation was assessed using the Cohen-Mansfield Agitation Inventory (CMAI). Health and social care costs of residing in care homes, and costs of contacts with health and social care services were calculated from national unit costs; for a societal perspective, costs of providing informal care were estimated using the resource utilization in dementia (RUD)-Lite scale. RESULTS: After adjustment, health and social care costs, and costs of providing informal care varied significantly by level of agitation as death approached, from £23,000 over a 1-year period with no agitation symptoms (CMAI agitation score 0-10) to £45,000 at the most severe level (CMAI agitation score >100). On average, agitation accounted for 30% of health and social care costs. Informal care costs were substantial, constituting 29% of total costs. CONCLUSIONS: With the increasing prevalence of dementia, costs of care will impact on healthcare and social services systems, as well as informal carers. Agitation is a key driver of these costs in people with advanced dementia presenting complex challenges for symptom management, service planners, and providers.

An evaluation of a veterinary-specific mental health service.

BACKGROUND: Veterinary professionals are at increased risk of suicide and mental health difficulties compared to the general population. Vetlife Health Support (VHS) is a mental health case management service for veterinarians with mental health difficulties. AIMS: To evaluate the VHS case management service from the service user's perspective. METHODS: Service users (n = 98) completed questionnaires assessing their experience with VHS and current mental health status using the Kessler-6 Scale. A sub-sample was interviewed and the data qualitatively analysed (n = 14). RESULTS: The results show that 97% (n = 95) reported a positive experience with VHS and 98% (n = 96) reported VHS staff respected and listened to them. Participants reported significant improvements in relationships with others after VHS (P < 0.001) and were significantly more likely to be in receipt of formal mental health care after VHS than before (P < 0.01). The main emergent themes from the qualitative interviews were (i) positive communication between clinician and service users, (ii) veterinary-specific mental health services were regarded as important to understanding service users' circumstances, (iii) knowing someone is supporting them positively impacted wellbeing and (iv) confusion with discharge status. CONCLUSIONS: Most participants reported positive experiences with VHS. Quantitatively, data showed that participants reported significant improvements in relationships and access to formal mental health care after contact with VHS. Interviews with service users revealed that they felt speaking to a mental health professional with veterinary-specific knowledge was beneficial for their wellbeing. Further evaluation assessing whether VHS leads to a measurable impact on psychological wellbeing is recommended.

Absence of the Musculocutaneous Nerve and Associated Compensation by the Median Nerve.

The musculocutaneous and median nerves frequently show variations from their normal course. The purpose of this paper is to report a rare variation, in which the right musculocutaneous nerve was absent. Consequently, the median nerve supplied motor innervation to the flexor compartment of the arm and sensory innervation to the lateral aspect of the forearm. The primary targets of this paper are orthopedic surgeons, anesthesiologists and radiologists. In cases of injuries to the upper limb, knowledge of these variations can assist them in avoiding misdiagnoses.

Treatment of patients with recurrent epithelial ovarian cancer for whom platinum is still an option.

BACKGROUND: Ovarian cancer remains the most deadly gynecologic cancer with the majority of patients relapsing within 3 years of diagnosis. Traditional treatment paradigms linked to platinum sensitivity or resistance are currently being questioned in the setting of new diagnostic methods and treatment options. DESIGN: Authors carried out review of the literature on key topics in treatment of recurrent epithelial ovarian cancer (EOC) when platinum is still an option; including secondary surgical cytoreduction, chemotherapy, novel treatment options, and maintenance therapy. A treatment algorithm is proposed. RESULTS: Molecular characterization of EOC is critical to help guide treatment decisions. The role of secondary cytoreductive surgery is currently being evaluated with results from Gynecologic Oncology Group (GOG) 213 and anticipated results from DESKTOP III clinical trials. Chemotherapy backbone has remained relatively unchanged but utilizing non-platinum-based regimens is under investigation. In addition, maintenance therapy with anti-angiogenic therapy and Poly (ADP-ribose) Polymerase (PARP) inhibitors has emerged as the standard of care. Novel combinations, including immunotherapy and anti-angiogenesis agents, may further change the current landscape. CONCLUSIONS: The treatment of recurrent EOC is rapidly changing. Clinical trial design will need to continue to evolve as many novel therapies move to the upfront setting. Ultimately, the treatment of patients with recurrent EOC must incorporate individual patient and tumor factors.

Mortality prediction following non-traumatic amputation of the lower extremity.

BACKGROUND: Patients who undergo lower extremity amputation secondary to the complications of diabetes or peripheral artery disease have poor long-term survival. Providing patients and surgeons with individual-patient, rather than population, survival estimates provides them with important information to make individualized treatment decisions. METHODS: Patients with peripheral artery disease and/or diabetes undergoing their first unilateral transmetatarsal, transtibial or transfemoral amputation were identified in the Veterans Affairs Surgical Quality Improvement Program (VASQIP) database. Stepdown logistic regression was used to develop a 1-year mortality risk prediction model from a list of 33 candidate predictors using data from three of five Department of Veterans Affairs national geographical regions. External geographical validation was performed using data from the remaining two regions. Calibration and discrimination were assessed in the development and validation samples. RESULTS: The development sample included 5028 patients and the validation sample 2140. The final mortality prediction model (AMPREDICT-Mortality) included amputation level, age, BMI, race, functional status, congestive heart failure, dialysis, blood urea nitrogen level, and white blood cell and platelet counts. The model fit in the validation sample was good. The area under the receiver operating characteristic (ROC) curve for the validation sample was 0·76 and Cox calibration regression indicated excellent calibration (slope 0·96, 95 per cent c.i. 0·85 to 1·06; intercept 0·02, 95 per cent c.i. -0·12 to 0·17). Given the external validation characteristics, the development and validation samples were combined, giving a total sample of 7168. CONCLUSION: The AMPREDICT-Mortality prediction model is a validated parsimonious model that can be used to inform the 1-year mortality risk following non-traumatic lower extremity amputation of patients with peripheral artery disease or diabetes.

Predicting reamputation risk in patients undergoing lower extremity amputation due to the complications of peripheral artery disease and/or diabetes.

BACKGROUND: Patients undergoing amputation of the lower extremity for the complications of peripheral artery disease and/or diabetes are at risk of treatment failure and the need for reamputation at a higher level. The aim of this study was to develop a patient-specific reamputation risk prediction model. METHODS: Patients with incident unilateral transmetatarsal, transtibial or transfemoral amputation between 2004 and 2014 secondary to diabetes and/or peripheral artery disease, and who survived 12 months after amputation, were identified using Veterans Health Administration databases. Procedure codes and natural language processing were used to define subsequent ipsilateral reamputation at the same or higher level. Stepdown logistic regression was used to develop the prediction model. It was then evaluated for calibration and discrimination by evaluating the goodness of fit, area under the receiver operating characteristic curve (AUC) and discrimination slope. RESULTS: Some 5260 patients were identified, of whom 1283 (24·4 per cent) underwent ipsilateral reamputation in the 12 months after initial amputation. Crude reamputation risks were 40·3, 25·9 and 9·7 per cent in the transmetatarsal, transtibial and transfemoral groups respectively. The final prediction model included 11 predictors (amputation level, sex, smoking, alcohol, rest pain, use of outpatient anticoagulants, diabetes, chronic obstructive pulmonary disease, white blood cell count, kidney failure and previous revascularization), along with four interaction terms. Evaluation of the prediction characteristics indicated good model calibration with goodness-of-fit testing, good discrimination (AUC 0·72) and a discrimination slope of 11·2 per cent. CONCLUSION: A prediction model was developed to calculate individual risk of primary healing failure and the need for reamputation surgery at each amputation level. This model may assist clinical decision-making regarding amputation-level selection.

Magneto-optic trap using a reversible, solid-state alkali-metal source.

We demonstrate a novel way to form and deplete a vapor-cell magneto-optic trap (MOT) using a reversible, solid-state alkali-metal source via an applied polarized voltage. Using ∼100 mW of electrical power, a trapped-atom number of 5×106 has been achieved, starting from near zero and the timescales of the MOT formation and depletion of ∼1 s. This fast, reversible, and low-power alkali-atom source is desirable in both tabletop and portable cold-atom systems. The core technology of this device should translate readily to other alkali and alkaline-earth elements that could find a wide range of uses in cold-atom systems and instruments.