Probing Ion-Receptor Interactions in Halide Complexes of Octamethyl Calix[4]Pyrrole.

Ion receptors are molecular hosts that bind ionic guests, often with great selectivity. The interplay of solvation and ion binding in anion host-guest complexes in solution governs the binding efficiency and selectivity of such ion receptors. To gain molecular-level insight into the intrinsic binding properties of octamethyl calix[4]pyrrole (omC4P) host molecules with halide guest ions, we performed cryogenic ion vibrational spectroscopy (CIVS) of omC4P in complexes with fluoride, chloride, and bromide ions. We interpret the spectra using density functional theory, describing the infrared spectra of these complexes with both harmonic and anharmonic second-order vibrational perturbation theory (VPT2) calculations. The NH stretching modes of the pyrrole moieties serve as sensitive probes of the ion binding properties, as their frequencies encode the ion-receptor interactions. While scaled harmonic spectra reproduce the experimental NH stretching modes of the chloride and bromide complexes in broad strokes, the high proton affinity of fluoride introduces strong anharmonic effects. As a result, the spectrum of F-·omC4P is not even qualitatively captured by harmonic calculations, but it is recovered very well by VPT2 calculations. In addition, the VPT2 calculations recover the intricate coupling of the NH stretching modes with overtones and combination bands of CH stretching and NH bending modes and with low-frequency vibrations of the omC4P macrocycle, which are apparent for all of the halide ion complexes investigated here. A comparison of the CIVS spectra with infrared spectra of solutions of the same ion-receptor complexes in d3-acetonitrile and d6-acetone shows how ion solvation changes the ion-receptor interactions for the different halide ions.

Prevention of foot ulcers in persons with diabetes at risk of ulceration: A systematic review and meta-analysis.

AIMS: Prevention of foot ulcers in persons with diabetes is important to help reduce the substantial burden on both individual and health resources. A comprehensive analysis of reported interventions is needed to better inform healthcare professionals about effective prevention. The aim of this systematic review and meta-analysis is to assess the effectiveness of interventions to prevent foot ulcers in persons with diabetes who are at risk thereof. MATERIALS AND METHODS: We searched the available scientific literature in PubMed, EMBASE, CINAHL, Cochrane databases and trial registries for original research studies on preventative interventions. Both controlled and non-controlled studies were eligible for selection. Two independent reviewers assessed risk of bias of controlled studies and extracted data. A meta-analysis (using Mantel-Haenszel's statistical method and random effect models) was done when >1 RCT was available that met our criteria. Evidence statements, including the certainty of evidence, were formulated according to GRADE. RESULTS: From the 19,349 records screened, 40 controlled studies (of which 33 were Randomised Controlled Trials [RCTs]) and 103 non-controlled studies were included. We found moderate certainty evidence that temperature monitoring (5 RCTs; risk ratio [RR]: 0.51; 95% CI: 0.31-0.84) and pressure-optimised therapeutic footwear or insoles (2 RCTs; RR: 0.62; 95% CI: 0.26-1.47) likely reduce the risk of plantar foot ulcer recurrence in people with diabetes at high risk. Further, we found low certainty evidence that structured education (5 RCTs; RR: 0.66; 95% CI: 0.37-1.19), therapeutic footwear (3 RCTs; RR: 0.53; 95% CI: 0.24-1.17), flexor tenotomy (1 RCT, 7 non-controlled studies, no meta-analysis), and integrated care (3 RCTs; RR: 0.78; 95% CI: 0.58-1.06) may reduce the risk of foot ulceration in people with diabetes at risk for foot ulceration. CONCLUSIONS: Various interventions for persons with diabetes at risk for foot ulceration with evidence of effectiveness are available, including temperature monitoring (pressure-optimised) therapeutic footwear, structured education, flexor tenotomy, and integrated foot care. With hardly any new intervention studies published in recent years, more effort to produce high-quality RCTs is urgently needed to further improve the evidence base. This is especially relevant for educational and psychological interventions, for integrated care approaches for persons at high risk of ulceration, and for interventions specifically targeting persons at low-to-moderate risk of ulceration.

Clinical and biomechanical effectiveness of foot-ankle exercise programs and weight-bearing activity in people with diabetes and neuropathy: A systematic review and meta-analysis.

BACKGROUND: Most interventions to prevent foot ulcers in people with diabetes do not seek to reverse the foot abnormalities that led to the ulcer. Foot-ankle exercise programs target these clinical and biomechanical factors, such as protective sensation and mechanical stress. Multiple RCTs exist investigating the effectiveness of such programs, but these have never been summarised in a systematic review and meta-analysis. METHODS: We searched the available scientific literature in PubMed, EMBASE, CINAHL, Cochrane databases and trial registries for original research studies on foot-ankle exercise programs for people with diabetes at risk of foot ulceration. Both controlled and non-controlled studies were eligible for selection. Two independent reviewers assessed the risk of bias of controlled studies and extracted data. Meta-analysis (using Mantel-Haenszel's statistical method and random effect models) was performed when >2 RCTs were available that met our criteria. Evidence statements, including the certainty of evidence, were formulated according to GRADE. RESULTS: We included a total of 29 studies, of which 16 were RCTs. A foot-ankle exercise programme of 8-12 weeks duration for people at risk of foot ulceration results in: (a) no increase or decrease risk of foot ulceration or pre-ulcerative lesion (Risk Ratio (RR): 0.56 (95% CI: 0.20-1.57)); (b) no increase or decrease risk of adverse events (RR: 1.04 (95% CI: 0.65-1.67)); (c) not increase or decrease barefoot peak plantar pressure during walking (Mean Difference (MD): -6.28 kPa (95% CI: -69.90-57.34)); (d) no increase or decrease health-related quality of life (no meta-analysis possible). Likely results in increases in ankle joint and first metatarsalphalangeal joint range of motion (MD: 1.49° (95% CI: -0.28-3.26)) may result in improvements in neuropathy signs and symptoms (MD: -1.42 (95% CI: -2.95-0.12)), may result in a small increase in daily steps in some people (MD: 131 steps (95% CI: -492-754)), and may not increase or decrease foot and ankle muscle strength and function (no meta-analysis was possible). CONCLUSIONS: In people at risk of foot ulceration, a foot-ankle exercise programme of 8-12 weeks duration may not prevent or cause diabetes-related foot ulceration. However, such a programme likely improves the ankle joint and first metatarsalphalangeal joint range of motion and neuropathy signs and symptoms. Further research is needed to strengthen the evidence base, and should also focus on the effects of specific components of foot-ankle exercise programs.

Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2023 update).

AIMS: This is the 2023 International Working Group on the Diabetic Foot guideline on the prevention of foot ulcers in persons with diabetes, which updates the 2019 guideline. This guideline is targeted at clinicians and other healthcare professionals. MATERIALS AND METHODS: We followed the Grading of Recommendations, Assessment, Development and Evaluations methodology to devise clinical questions and critically important outcomes in the PICO format, to conduct a systematic review of the medical-scientific literature including, where appropriate, meta-analyses, and to write recommendations and their rationale. The recommendations are based on the quality of evidence found in the systematic review, expert opinion where (sufficient) evidence was not available, and a weighing of the desirable and undesirable effects of an intervention, as well as patient preferences, costs, equity, feasibility and applicability. RESULTS: We recommend screening a person with diabetes at very low risk of foot ulceration annually for the loss of protective sensation and peripheral artery disease, and screening persons at higher risk at higher frequencies for additional risk factors. For preventing a foot ulcer, educate persons at-risk about appropriate foot self-care, educate not to walk without suitable foot protection, and treat any pre-ulcerative lesion on the foot. Educate moderate-to-high risk people with diabetes to wear properly fitting, accommodative, therapeutic footwear, and consider coaching them to monitor foot skin temperature. Prescribe therapeutic footwear that has a demonstrated plantar pressure relieving effect during walking, to help prevent plantar foot ulcer recurrence. Consider advising people at low-to-moderate risk to undertake a, preferably supervised, foot-ankle exercise programme to reduce ulcer risk factors, and consider communicating that a total increase in weight-bearing activity of 1000 steps/day is likely safe with regards to risk of ulceration. In people with non-rigid hammertoe with pre-ulcerative lesion, consider flexor tendon tenotomy. We suggest not to use a nerve decompression procedure to help prevent foot ulcers. Provide integrated foot care for moderate-to-high-risk people with diabetes to help prevent (recurrence of) ulceration. CONCLUSIONS: These recommendations should help healthcare professionals to provide better care for persons with diabetes at risk of foot ulceration, to increase the number of ulcer-free days and reduce the patient and healthcare burden of diabetes-related foot disease.

Competition between Water-Water Hydrogen Bonds and Water-π Bonds in Pyrene-Water Cluster Anions.

We present infrared spectra and density functional theory calculations of hydrated pyrene anion clusters with up to four water molecules. The experimental spectra were acquired by using infrared Ar messenger photodissociation spectroscopy. Water molecules form clusters on the surface of the pyrene, forming hydrogen bonds with the π-system. The structures of the water clusters and their interaction with the π-system are encoded in OH stretching vibrational modes. We find that the interactions between water molecules are stronger than the interactions between water molecules and the π-system. While all clusters show multiple conformers, three- and four-membered rings are the lowest energy structures in the larger hydrates.

Prenatal and early childhood predictors of intelligence quotient (IQ) in 7-year-old Danish children from the Odense Child Cohort.

BACKGROUND: Cognitive development measured as intelligence quotient can predict socioeconomic markers in adulthood. It is therefore of interest to determine predictors of childhood intelligence quotient. AIM: To assess intelligence quotient scores based on standardised Danish age-appropriate scores and to evaluate potential predictors of intelligence quotient. MATERIALS: At 7 years of age children in the Odense Child Cohort completed an abbreviated version of the Wechsler intelligence scale for children 5th edition consisting of four subtests (vocabulary, similarities, block design and matrix reasoning) from which the full scale intelligence quotient and verbal comprehension index were estimated. Potential predictors from pregnancy through childhood were collected from questionnaires, birth records and clinical examinations. METHODS: Intelligence quotient scores were investigated through descriptive statistics and linear regression models. RESULTS: The mean full scale intelligence quotient among 1375 children was 99.1 (95% confidence interval 98.5; 99.8) points. Higher full scale intelligence quotient scores were observed in girls 100.8 (95% confidence interval 100.0; 101.8) compared to boys 97.6 (96.7; 98.4), and in children of mothers with high and intermediate education 101.7 (100.4; 103.1) and 99.6 (98.7; 100.5), respectively, compared to low education 96.1 (94.9; 97.3). In linear regression analyses, longer maternal education and child sex (girls) remained strong predictors of intelligence quotient at age 7 years. In addition, paternal education, child head circumference and longer duration of breastfeeding were associated with higher intelligence quotient, whereas maternal overweight and obesity before pregnancy was associated with lower intelligence quotient. CONCLUSIONS: Mean intelligence quotient scores were comparable to the standardised mean intelligence quotient of 100 point of Danish peers. It is important to follow up these children to determine which predictors persist into adulthood.

Light Driven Ultrafast Bioinspired Molecular Motors: Steering and Accelerating Photoisomerization Dynamics of Retinal.

Photoisomerization of retinal protonated Schiff base in microbial and animal rhodopsins are strikingly ultrafast and highly specific. Both protein environments provide conditions for fine-tuning the photochemistry of their chromophores. Here, by combining time-resolved action absorption spectroscopy and high-level electronic structure theory, we show that similar control can be gained in a synthetically engineered retinal chromophore. By locking the dimethylated retinal Schiff base at the C11═C12 double bond in its trans configuration (L-RSB), the excited-state decay is rendered from a slow picosecond to an ultrafast subpicosecond regime in the gas phase. Steric hindrance and pretwisting of L-RSB are found to be important for a significant reduction in the excited-state energy barriers, where isomerization of the locked chromophore proceeds along C9═C10 rather than the preferred C11═C12 isomerization path. Remarkably, the accelerated excited-state dynamics also becomes steered. We show that L-RSB is capable of unidirectional 360° rotation from all-trans to 9-cis and from 9-cis to all-trans in only two distinct steps induced by consecutive absorption of two 600 nm photons. This opens a way for the rational design of red-light-driven ultrafast molecular rotary motors based on locked retinal chromophores.

Nonepithelial ovarian cancer - the current clinical practice in the Nordic countries. Survey from the surgical subcommittee of the Nordic society of gynecological oncology (NSGO).

BACKGROUND: Nonepithelial ovarian cancer (NEOC) represents a wide variety of rare tumors. They are often diagnosed at an early stage and have a good prognosis compared to epithelial ovarian cancer. In the Nordic countries, the total annual number of patients diagnosed with ovarian cancer, Fallopian tube cancer or primary peritoneal carcinoma (hereafter ovarian cancer) was 2281 in 2014-2018, of which 3-10% were NEOC. International guidelines for diagnosis, treatment and follow-up have been developed. We present the results of a survey, aiming at clarifying current clinical practice in the Nordic countries. MATERIAL AND METHODS: Between 09.2020 and 02.2021 a 33-question electronic survey was distributed to 22 hospitals in Finland, Sweden, Norway, Iceland and Denmark via the Nordic Society of Gynecological Oncology (NSGO) National Representatives. Data were collected in a secure web-based software platform. The questionnaire focused on demographics, diagnosis, treatment and follow-up programs. RESULTS: Twenty-one (95,4%) centers completed the survey. A total of 155 annual new NEOC cases treated in the Nordic countries were reported, corresponding to approximately 7% of all ovarian cancer cases. Most centers measured some or all of the recommended biomarkers routinely. Vaginal ultrasound and computed tomography (CT) were the preferred imaging modalities. The majority of centers conducted multidisciplinary team (MDT) meetings. The primary reported treatment was surgery. In 65% of centers, lymph node dissection was only performed in cases with suspicious lymph nodes. Surveillance was usually offered > four years. DISCUSSION: Despite, the presence of clinical European guidelines, variation in the current clinical practice amongst participating centers adhering to national guidelines was observed. Prospective clinical national research programs are sparse, and an enhanced cooperation in the Nordic countries toward development of a Nordic guideline and database is highly warranted and a prerequisite for future research, preferably in cooperation with the larger international groups.

The memories that people would save or erase differ from their most positive and negative memories on function, emotion and correspondence with the life script.

Autobiographical remembering is a dynamic process in which narrators construct their life story from single memories. What is included in or deleted from the life story depends on many factors. Here, we examined the functions, emotions and correspondence with the life script for the memories that people desire to save or erase from their past. We asked people to generate either the two memories they were most likely to save and erase or the two memories they regarded as their most positive and negative memories. Then everyone rated those memories on function, emotion and correspondence with the life script. Overall, we found save and erase memories corresponded less with the life script relative to most positive and most negative memories though they were similarly emotionally intense. Additionally, erase memories were more associated with shame and less with social functions than most negative memories, whereas most negative memories to a higher degree involved the death of significant others, albeit being similarly traumatic. These findings have important implications for theory about autobiographical memory, and possible clinical relevance.

Spectroscopy and photoisomerization of protonated Schiff-base retinal derivatives in vacuo.

The protonated Schiff-base retinal acts as the chromophore in bacteriorhodopsin as well as in rhodopsin. In both cases, photoexcitation initializes fast isomerization which eventually results in storage of chemical energy or signaling. The details of the photophysics for this important chromophore is still not fully understood. In this study, action-absorption spectra and photoisomerization dynamics of three retinal derivatives are measured in the gas phase and compared to that of the protonated Schiff-base retinal. The retinal derivatives include C9C10trans-locked, C13C14trans-locked and a retinal derivative without the ß-ionone ring. The spectroscopy as well as the isomerization speed of the chromophores are altered significantly as a consequence of the steric constraints.

Elevated miR-615-3p Expression Predicts Adverse Clinical Outcome and Promotes Proliferation and Migration of Prostate Cancer Cells.

miR-615-3p has previously been described as up-regulated in prostate cancer (PC) tissue samples compared with nonmalignant controls; however, its prognostic potential and functional role in PC remain largely unknown. In this study, we investigated the clinical and biological relevance of miR-615-3p in PC. The expression of miR-615-3p was measured in PC tissue specimens from 239 men who underwent radical prostatectomy (RP), and it was investigated if miR-615-3p could predict postoperative biochemical recurrence (BCR). These findings were subsequently validated in three independent RP cohorts (n = 222, n = 273, and n = 387) and functional overexpression studies conducted in PC cells (PC3M). High miR-615-3p expression was significantly associated with BCR in four independent PC patient cohorts (P < 0.05, log-rank test). In addition, high miR-615-3p expression was a significant predictor of PC-specific survival in univariate (hazard ratio, 3.75; P < 0.001) and multivariate (hazard ratio, 2.66; P = 0.008) analysis after adjustment for the Cancer of the Prostate Risk Assessment Post-Surgical (CAPRA-S) nomogram in a merged RP cohort (n = 734). Moreover, overexpression of miR-615-3p in PC cells (PC3M) significantly increased cell viability, proliferation, apoptosis, and migration. Together, our results suggest that miR-615-3p is a significant predictor of postoperative BCR and PC-specific survival and has oncogenic functions in PC cells.

Prevention of foot ulcers in the at-risk patient with diabetes: a systematic review.

Prevention of foot ulcers in patients with diabetes is important to help reduce the substantial burden on both patient and health resources. A comprehensive analysis of reported interventions is needed to better inform healthcare professionals about effective prevention. The aim of this systematic review is to investigate the effectiveness of interventions to help prevent both first and recurrent foot ulcers in persons with diabetes who are at risk for this complication. We searched the available medical scientific literature in PubMed, EMBASE, CINAHL, and the Cochrane databases for original research studies on preventative interventions. We screened trial registries for additional studies not found in our search and unpublished trials. Two independent reviewers assessed data from controlled studies for methodological quality, and extracted and presented this in evidence and risk of bias tables. From the 13,490 records screened, 35 controlled studies and 46 non-controlled studies were included. Few controlled studies, which were of generally low to moderate quality, were identified on the prevention of a first foot ulcer. For the prevention of recurrent plantar foot ulcers, there is benefit for the use of daily foot skin temperature measurements, and for therapeutic footwear with demonstrated plantar pressure relief, provided it is consistently worn by the patient. For prevention of ulcer recurrence, there is some evidence for providing integrated foot care, and no evidence for a single session of education.Surgical interventions have been shown effective in selected patients, but the evidence base is small. Foot-related exercises do not appear to prevent a first foot ulcer. A small increase in the level of weight-bearing daily activities does not seem to increase the risk for foot ulceration. The evidence base to support the use of specific self-management and footwear interventions for the prevention of recurrent plantar foot ulcers is quite strong. The evidence is weak for the use of other, sometimes widely applied, interventions, and is practically non-existent for the prevention of a first foot ulcer and non-plantar foot ulcer.

Treatment of modifiable risk factors for foot ulceration in persons with diabetes: a systematic review.

BACKGROUND: Prevention of diabetic foot ulcers is important. Preventative treatment mostly targets and aims to improve modifiable risk factors of foot ulceration. While effectiveness of interventions in ulcer prevention has been systematically reviewed, their effectiveness in improving modifiable risk factors is unknown. METHODS: The available medical scientific literature in PubMed, Excerpta Medica Database, and the Cochrane database was searched for original research studies on six interventions to treat modifiable risk factors for diabetic foot ulceration (ie, education for patients; education for professionals; self-management; pre-ulcer treatment; orthotic interventions; and foot- and mobility-related exercises). We assessed interventions for eight outcomes (ie, patients' knowledge; treatment adherence; professionals' knowledge; pre-ulcers; mechanical stress; neuropathy symptoms; foot/ankle joint mobility; and foot function). Both controlled and noncontrolled studies were selected. Data from controlled studies were assessed for methodological quality by two independent reviewers and extracted and presented in evidence and risk of bias tables. RESULTS: We included 72 publications (26 with a controlled study design and 46 noncontrolled). We found that structured education may improve foot self-care behaviour of patients, yearly foot examinations, and foot disease knowledge of health care professionals. Callus removal reduces peak plantar pressure. Custom-made therapeutic footwear can be effective in reducing plantar pressure and may reduce callus. Foot- and mobility-related exercises may improve neuropathy symptoms and foot and ankle joint range of motion, while they do not seem to reduce peak plantar pressure; evidence for their effect on foot strength is conflicting. CONCLUSIONS: Structured education for patients and health care professionals, callus removal, custom-made therapeutic footwear, and foot- and mobility-related exercises may be beneficial for improving modifiable risk factors for foot ulceration. However, we generally found low quality of evidence for interventions targeting modifiable risk factors for ulceration in persons with diabetes, with frequently inconsistent or limited results available per intervention and outcome.

Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 update).

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. This guideline is on the prevention of foot ulceration in persons with diabetes and updates the 2015 IWGDF prevention guideline. We followed the GRADE methodology to devise clinical questions and critically important outcomes in the PICO format, to conduct a systematic review of the medical-scientific literature, and to write recommendations and their rationale. The recommendations are based on the quality of evidence found in the systematic review, expert opinion where evidence was not available, and a weighing of the benefits and harms, patient preferences, feasibility and applicability, and costs related to the intervention. We recommend to screen a person at very low risk for ulceration annually for loss of protective sensation and peripheral artery disease and persons at higher risk at higher frequencies for additional risk factors. For preventing a foot ulcer, educate the at-risk patient about appropriate foot self-care and treat any pre-ulcerative sign on the foot. Instruct moderate-to-high risk patients to wear accommodative properly fitting therapeutic footwear, and consider instructing them to monitor foot skin temperature. Prescribe therapeutic footwear that has a demonstrated plantar pressure relieving effect during walking to prevent plantar foot ulcer recurrence. In patients that fail non-surgical treatment for an active or imminent ulcer, consider surgical intervention; we suggest not to use a nerve decompression procedure. Provide integrated foot care for high-risk patients to prevent ulcer recurrence. Following these recommendations will help health care professionals to provide better care for persons with diabetes at risk of foot ulceration, to increase the number of ulcer-free days, and to reduce the patient and health care burden of diabetic foot disease.

Appendectomy, cholecystectomy and diagnostic laparoscopy conducted before pregnancy and risk of adverse birth outcomes: a nationwide registry-based prevalence study 1996-2015.

BACKGROUND: Non-obstetric surgery conducted during pregnancy may increase the risk of adverse birth outcomes like small for gestational age, preterm birth, and miscarriage. Mechanisms are unclear but possibly longer lasting. We examined whether appendectomy, cholecystectomy and diagnostic laparoscopy conducted before pregnancy affect these outcomes. METHODS: This nationwide Danish prevalence study included all pregnancies during 1996-2015 that had an appendectomy, cholecystectomy or diagnostic laparoscopy registered before last menstrual period in the years 1992-2015. We excluded pregnancies with surgery and categorized pre-pregnancy surgery according to timing (0-11, 12-23, and 24+ months before last menstrual period). Outcomes were small for gestational age, late preterm birth (32-37 weeks), early preterm birth (22-31 weeks) and miscarriage (7-21 weeks). We computed absolute risks and used logistic regression comparing pregnancies with surgery 0-11 or 12-23 to 24+ months before last menstrual period, computing odds ratios for each outcome, adjusting for maternal age and smoking. RESULTS: We identified 15,939 pregnancies with appendectomy, 12,869 pregnancies with cholecystectomy and 19,330 pregnancies with diagnostic laparoscopy. The absolute risk of small for gestational age was 2.2% for patients with appendectomy 0-11 months before last menstrual period, 3.2% 12-23 months before compared with 2.2% when appendectomy was conducted more than 24 months before (adjusted OR 0.95 (95% CI; 0.65 to 1.31) and 1.37(95% CI;1.00 to 1.86). For early preterm birth, the absolute risks were 0.7, 0.5 and 0.8%, for late preterm birth 4.8, 4.4 and 4.7% and for miscarriage 5.7, 6.2 and 5.4%.We observed similar results for cholecystectomy. For diagnostic laparoscopy 0-11 months before pregnancy we found increased risks of small for gestational age (4.0, 2.8 and 2.6%) and late preterm birth (5.9, 5.0 and 4.8%). CONCLUSIONS: We found no increased risk of adverse birth outcomes among pregnancies with appendectomy or cholecystectomy conducted within 2 years before pregnancy compared to more than 2 years before pregnancy. The increased risks 0-11 months after diagnostic laparoscopy are likely explained by confounding by underlying indication. It appears safe to become pregnant any time following appendectomy and cholecystectomy, but, probably depending on indication, attention should be payed 0-11 months after diagnostic laparoscopy.

Non-obstetric abdominal surgery during pregnancy and birth outcomes: A Danish registry-based cohort study.

INTRODUCTION: Surgery during pregnancy may increase the risk of adverse birth outcomes. In this nationwide registry-based cohort study including women aged 15-54 years with singleton birth or miscarriage, we examined the association between non-obstetric abdominal surgery during pregnancy and the birth outcomes small-for-gestational-age (SGA), preterm birth, and miscarriage. MATERIAL AND METHODS: The study used data on births or miscarriages from the large national Danish registries in 1997-2015. We calculated absolute risks and risk differences for the main outcomes and used Cox regression analysis with non-obstetric abdominal surgery as a time-varying exposure, adjusting for maternal age, year of last menstrual period, major abdominal surgery before pregnancy, maternal smoking status, rheumatoid arthritis, diabetes and inflammatory bowel disease. Our main outcome measures were risks and hazard ratios (HRs) for SGA, very preterm or preterm birth, and miscarriage after gestational week 7 overall, stratified by calendar year, and, for SGA, trimester of pregnancy. Finally, absolute risk of miscarriage stratified by time since surgery. RESULTS: Absolute risks in surgically treated vs untreated were 3.4% vs 2.7% for SGA (adjusted HR 1.3, 95% CI 1.1-1.5), 2.2% vs 0.8% for very preterm birth (adjusted HR 2.8, 95% CI 2.2-3.5), 8.3% vs 4.3% for preterm birth (adjusted HR 2.1, 95% CI 1.9-2.3), and 8.2% vs 6.1% for miscarriage (adjusted HR 3.1, 95% CI 2.7-3.5). For miscarriage, the risk was highest the first week after surgery and levelled out after 2 weeks. CONCLUSIONS: Surgery during pregnancy is associated with an increased risk of SGA, very preterm birth, preterm birth and miscarriage, and the risk of miscarriage is highest the first week after surgery.

Negative memories serve functions in both adaptive and maladaptive ways.

Autobiographical memories are said to serve at least three functions: they direct people's behaviour, inform their identity, and facilitate social bonding and communication. But much of the research on these three functions has not distinguished between memories that serve functions in adaptive ways from those that serve functions in maladaptive ways. Across two experiments, we asked subjects to provide either positive or negative memories. Then, to operationalise adaptive and maladaptive functions, we asked subjects to rate the extent to which those memories serve directive, self, and social functions in ways that "help" and in ways that "hurt". To investigate whether people believe the adaptive benefits of their memories outweigh any maladaptive effects, we also asked subjects how willing they would be to erase the memories if given the opportunity. We found that negative memories served functions in both helpful and hurtful ways, whereas positive memories were primarily helpful. Furthermore, the more helpful a memory was, the more reluctant subjects were to erase it. Conversely, the more hurtful a memory was, the more willing subjects were to erase it. These results suggest it is important to distinguish between adaptive and maladaptive functions when investigating the functions of autobiographical memory.

Typhoid and the Military in the Early 20th Century.

BACKGROUND: In the decades following the discovery of the bacillus causing typhoid, in 1880, understanding of the disease formerly known as enteric fever was transformed, offering new possibilities for prevention. Gradually, measures that aimed to prevent infection from human carriers were developed, as were inoculations designed to confer immunity against typhoid and paratyphoid fevers. These were initially introduced in European armies that were regularly ravaged by typhoid, especially garrisons stationed in the colonies. This article reviews the research undertaken in the armed forces and the measures that they implemented in the years up to and during the First World War. METHODS: The article is based on an analytical review of scientific literature from the early 19th century, focusing on the United Kingdom, Germany, and France. RESULTS: The armies of the United Kingdom, Germany, and France undertook important work on the transmission of typhoid in the years between 1890 and 1918. Many preventive measures were introduced to deal with the spread of typhoid but these varied between the 3 countries, depending largely on their political traditions. Inoculation was particularly successful in preventing typhoid and greatly reduced the number of casualties from this disease during the First World War. Despite this, it proved difficult to prevent paratyphoid infection, and debates continued over which vaccines to use and whether or not immunization should be voluntary. CONCLUSIONS: By the end of the First World War, the value of inoculation in preventing the spread of typhoid had been proven. Its successful implementation demonstrates the importance of vaccination as a public health intervention during times of conflict and social upheaval.

A five-microRNA model (pCaP) for predicting prostate cancer aggressiveness using cell-free urine.

Improved biomarkers for prostate cancer (PC) risk stratification are urgently needed. Here, we aimed to develop a novel multimarker model for prediction of biochemical recurrence (BCR) after curatively intended radical prostatectomy (RP), based on minimally invasive sampling of blood and urine. We initially measured the levels of 45 selected miRNAs by RT-qPCR in exosome enriched cell-free urine samples collected prior to RP from 215 PC patients (Cohort 1, training). We trained a novel logistic regression model (pCaP), comprising five urine miRNAs (miR-151a-5p, miR-204-5p, miR-222-3p, miR-23b-3p and miR-331-3p) and serum prostate-specific antigen (PSA), which significantly predicted time to BCR in Cohort 1 (univariate Cox regression analysis: HR = 3.12, p < 0.001). Next, using the same exact numeric cutoff for dichotomization as trained in Cohort 1, we tested and successfully validated the prognostic potential of pCaP in two additional cohorts, including 199 (Cohort 2, HR = 2.24, p = 0.002) and 205 (Cohort 3, HR = 2.15, p = 0.004) RP patients, respectively. pCaP remained a significant predictor of BCR, also after adjustment for pathological T-stage, surgical margin status and Gleason grade group (p < 0.05 in multivariate Cox regression analysis: HR = 2.72, 1.94 and 1.83 for Cohorts 1, 2 and 3, respectively). Additionally, pCaP scores correlated positively with the established clinical risk stratification nomogram CAPRA in all three PC cohorts (Pearson's rho: 0.45, 0.39 and 0.44). Together, our results suggest that the minimally invasive pCaP model could potentially be used in the future to improve PC risk stratification and to guide more personalized treatment decisions. Further clinical validation studies are warranted.