Formation of a conceptual framework during the development of a patient-reported outcome measure for early gastrointestinal recovery: phase I of the PRO-diGi study.

AIM: Patients admitted to hospital for abdominal surgery often experience gastrointestinal dysfunction. Many studies have reported outcomes following gastrointestinal dysfunction, yet there is no unified definition of recovery or a validated patient-reported outcome measure (PROM). The first stage of PROM development requires formation of a conceptual framework to identify key themes to patients. The aim of this study was to utilize semistructured interviews to identify core themes and concepts relevant to patients to facilitate development of a conceptual framework. METHOD: Adult patients admitted to hospital for major gastrointestinal, urological or gynaecological surgery, in an emergency or elective setting, were eligible to participate. Patients treated nonoperatively for small bowel obstruction were also eligible. Interviews were conducted by telephone, audio-recorded, transcribed, coded and analysed using NVivo software by two researchers and reviewed by lay members of the steering group. Interviews continued until data saturation was reached. Ethical approval was gained prior to interviews (21/WA/0231). RESULTS: Twenty nine interviews were completed (17 men, median age 64 years) across three specialties (20 gastrointestinal, six gynaecological, three urological). Two overarching themes of 'general recovery' and 'gastrointestinal symptoms' were identified. General recovery included three themes: 'life impact', 'mental impact', including anxiety, and 'physical impact', including fatigue. Gastrointestinal symptoms included three themes: 'abdominal symptoms' such as pain, 'diet and appetite' and 'expulsory function', such as stool frequency. A total of 18 gastrointestinal symptoms were identified during patient recovery-many of which lasted several weeks following discharge. CONCLUSION: This study reports a range of gastrointestinal and nongastrointestinal symptoms experienced by patients during early gastrointestinal recovery. Identified symptoms have been synthesized into a conceptual framework to enable development of a definitive PROM for early gastrointestinal recovery.

The Young were not Spared: What Death Certificates Reveal about Non-Covid Excess Deaths.

From April 2020 through at least the end of 2021, Americans died from non-Covid causes at an average annual rate of 97 000 in excess of previous trends. Hypertension and heart disease deaths combined were elevated 32 000. Diabetes or obesity, drug-induced causes, and alcohol-induced causes were each elevated 12 000 to 15 000 above previous (upward) trends. Drug deaths especially followed an alarming trend, only to significantly exceed it during the pandemic to reach 108 000 for calendar year 2021. Homicide and motor-vehicle fatalities combined were elevated almost 10 000. Various other causes combined to add 18 000. While Covid deaths overwhelmingly afflict senior citizens, absolute numbers of non-Covid excess deaths are similar for each of the 18 to 44, 45 to 64, and over-65 age groups, with essentially no aggregate excess deaths of children. Mortality from all causes during the pandemic was elevated 26% for working-age adults (18-64), as compared to 18% for the elderly. Other data on drug addictions, non-fatal shootings, weight gain, and cancer screenings point to a historic, yet largely unacknowledged, health emergency.

Genetic origins of the Minoans and Mycenaeans.

The origins of the Bronze Age Minoan and Mycenaean cultures have puzzled archaeologists for more than a century. We have assembled genome-wide data from 19 ancient individuals, including Minoans from Crete, Mycenaeans from mainland Greece, and their eastern neighbours from southwestern Anatolia. Here we show that Minoans and Mycenaeans were genetically similar, having at least three-quarters of their ancestry from the first Neolithic farmers of western Anatolia and the Aegean, and most of the remainder from ancient populations related to those of the Caucasus and Iran. However, the Mycenaeans differed from Minoans in deriving additional ancestry from an ultimate source related to the hunter-gatherers of eastern Europe and Siberia, introduced via a proximal source related to the inhabitants of either the Eurasian steppe or Armenia. Modern Greeks resemble the Mycenaeans, but with some additional dilution of the Early Neolithic ancestry. Our results support the idea of continuity but not isolation in the history of populations of the Aegean, before and after the time of its earliest civilizations.

Circulating interleukin-18 as a biomarker of total-body radiation exposure in mice, minipigs, and nonhuman primates (NHP).

We aim to develop a rapid, easy-to-use, inexpensive and accurate radiation dose-assessment assay that tests easily obtained samples (e.g., blood) to triage and track radiological casualties, and to evaluate the radioprotective and therapeutic effects of radiation countermeasures. In the present study, we evaluated the interleukin (IL)-1 family of cytokines, IL-1ß, IL-18 and IL-33, as well as their secondary cytokines' expression and secretion in CD2F1 mouse bone marrow (BM), spleen, thymus and serum in response to γ-radiation from sublethal to lethal doses (5, 7, 8, 9, 10, or 12 Gy) at different time points using the enzyme-linked immune sorbent assay (ELISA), immunoblotting, and cytokine antibody array. Our data identified increases of IL-1ß, IL-18, and/or IL-33 in mouse thymus, spleen and BM cells after total-body irradiation (TBI). However, levels of these cytokines varied in different tissues. Interestingly, IL-18 but not IL-1ß or IL-33 increased significantly (2.5-24 fold) and stably in mouse serum from day 1 after TBI up to 13 days in a radiation dose-dependent manner. We further confirmed our finding in total-body γ-irradiated nonhuman primates (NHPs) and minipigs, and demonstrated that radiation significantly enhanced IL-18 in serum from NHPs 2-4 days post-irradiation and in minipig plasma 1-3 days post-irradiation. Finally, we compared circulating IL-18 with the well known hematological radiation biomarkers lymphocyte and neutrophil counts in blood of mouse, minipigs and NHPs and demonstrated close correlations between these biomarkers in response to radiation. Our results suggest that the elevated levels of circulating IL-18 after radiation proportionally reflect radiation dose and severity of radiation injury and may be used both as a potential biomarker for triage and also to track casualties after radiological accidents as well as for therapeutic radiation exposure.

Description and genetic analysis of three sets of monozygotic twins resulting from transfers of single embryos to recipient mares.

CASE DESCRIPTION: 3 sets of monozygotic twins resulting from transfers of single embryos to recipient mares were examined. CLINICAL FINDINGS: In all 3 recipient mares with twin pregnancies, only 1 embryonic vesicle was detected before day 25 of gestation. In 1 recipient mare, 2 apparent adjacent vesicles, each containing an embryo with a heartbeat, were visualized on ultrasonographic examination on day 37 of gestation. The other 2 recipient mares underwent ultrasonographic examination on day 30 of gestation, at which time only 1 vesicle and embryo was identified. In these latter 2 recipient mares, however, a thorough ultrasonographic examination for a second conceptus on day 30 had not been performed, as only 1 embryo had been transferred and visualized on early ultrasonographic examination. TREATMENT AND OUTCOME: All twin pregnancies resulted in death of both fetuses. Genetic analysis confirmed that each set of monozygotic twins originated from the transferred embryo. CLINICAL RELEVANCE: Monozygotic twin pregnancy may occur after embryo transfer; thus recipient mares should be examined thoroughly for multiple conceptuses, especially between 25 and 30 days of gestation. At this time, the allantoides of monozygotic twins should be visible ultrasonographically and effective management may still be possible.

Sensitivity to interaural correlation of single neurons in the inferior colliculus of guinea pigs.

Sensitivity to changes in the interaural correlation of 50-ms bursts of narrowband or broadband noise was measured in single neurons in the inferior colliculus of urethane-anaesthetized guinea pigs. Rate vs. interaural correlation functions (rICFs) were measured using two methods. These methods compensated in different ways for the inherent variance in interaural correlation between tokens with the same expected correlation. The shape of all rICFs could be best described by power functions allowing them to be summarized by two parameters. Most rICFs were best fit by a power below 2, indicating that they were only slightly nonlinear. However, there were a few fitted functions that had a power of 3-6, indicating marked curvature. Modeling results indicate that the nonlinearity of the majority of rICFs was explicable in terms of the monaural transduction stages; however, some of the rICFs with power greater than 2 require either multiple inputs to the coincidence detector or additional nonlinearities to be included in the model. Discrimination thresholds were estimated at reference correlations of -1, 0, and +1 using receiver operating characteristic (ROC) analysis of the spike-count distribution at each correlation. Thresholds spanned the full possible range, from a minimum of 0.1 to the maximum possible of 2. Thresholds were generally highest with a reference correlation of -1, intermediate with a reference of 0, and lowest with a reference correlation of +1. Thresholds were lowest for the most steeply sloped rICFs, but thresholds were not strongly correlated to the spike rate variance. The lowest thresholds occurred using narrowband noise that was compensated for internal delays, but they were still about three times larger than human psychophysical thresholds measured using similar stimuli. The data suggest that, unlike pure tone interaural time difference, discrimination of a population measure is required to account for behavioral interaural correlation discrimination performance.

A stone at the Siege of Cyropolis and the death of Alexander the Great.

Alexander the Great was struck by a stone at the Siege of Cyropolis in 329 BC and was rendered temporarily blind and inaudible as a result. Although other authors have written extensively about the likely pathological effects of this injury, none have suggested carotid artery dissection as a possible cause. We present evidence that this should be considered as a differential diagnosis and how it might explain an unusual symptom seen at his deathbed in Babylon six years later.

Onset neurones in the anteroventral cochlear nucleus project to the dorsal cochlear nucleus.

Considerable circumstantial evidence suggests that cells in the ventral cochlear nucleus, that respond predominantly to the onset of pure tone bursts, have a stellate morphology and project, among other places, to the dorsal cochlear nucleus. The characteristics of such cells make them leading candidates for providing the so-called "wideband inhibitory input" which is an essential part of the processing machinery of the dorsal cochlear nucleus. Here we use juxtacellular labeling with biocytin to demonstrate directly that large stellate cells, with onset responses, terminate profusely in the dorsal cochlear nucleus. They also provide widespread local innervation of the anteroventral cochlear nucleus and a small innervation of the posteroventral cochlear nucleus. In addition, some onset cells project to the contralateral dorsal cochlear nucleus.

Interaural time difference discrimination thresholds for single neurons in the inferior colliculus of Guinea pigs.

Sensitivity to changes in the interaural time difference (ITD) of 50 msec tones was measured in single units in the inferior colliculus of urethane-anesthetized guinea pigs. ITD functions were measured with 100 repeats and fine spacing (100 points per cycle). The just noticeable difference (jnd) for ITD was determined using receiver operating characteristic (ROC) analysis of the spike-count distribution at each ITD. The jnd became progressively smaller as the signal frequency increased from 50 to 800 Hz but became unmeasurable above 1 kHz. The lowest jnds (30 microsec) were comparable with human jnds, indicating that there is sufficient information in the firings of individual neurons to permit discrimination without obligatory pooling. ROC analysis requires the choice of a reference ITD from which the jnd may be found by stepping the target ITD through the ITD function. For each neuron the reference was chosen to minimize the jnd. The lowest jnd was usually for ipsilateral leading references, near the minimum of the ITD function where the variance was also low, but where the slope was nearing its steepest. This was despite the peak of the ITD function occurring for contralateral leading stimuli. When the reference ITD was on midline, a jnd could be obtained by looking for firing rates either greater or smaller than the firing rate at midline. The lower jnd was usually obtained by looking for a decrease in firing rate. As duration increased, jnds either decreased or increased, depending on unit type, whereas when level increased, jnds generally increased.