Ultrasound skills teaching in UK medical education: A systematic review.

BACKGROUND: Sonography is increasingly integrated into medical curricula to prepare students for clinical practice. In 2022, we conducted a systematic review to explore the degree to which ultrasound skill acquisition is incorporated into undergraduate medial education in the United Kingdom. METHODS: A search of Medline and Embase databases from 2003 to 2022 identified 15 relevant articles. Studies were included if they described ultrasound skills training in UK undergraduate medical education. FINDINGS: A range of teaching methods were reported including didactic demonstrations, hands-on experience and combinations thereof. Portable machines were more common than cart-based machines, and most demonstrators were ultrasound-trained clinicians. Ultrasound teaching is well received, with improvements in confidence using ultrasound, motivation to learn anatomy and retention of knowledge. DISCUSSION: Obstacles to integration were noted including training, cost, curriculum time constraints and the issue of incidental pathology. One study demonstrated that anatomists with appropriate training could provide ultrasound teaching, reducing the need for clinicians or sonographers. Costs may be reduced by renting machines or purchasing portable/hand-held devices. Allowing access to machines during student's free time may address scheduling difficulties. A final recommendation is to pre-scan volunteers prior to the teaching session. CONCLUSION: We have outlined approaches to ultrasound skills teaching and the inherent hurdles to this, as well as potential solutions. This may aid educators wishing to augment their curricula. Although there are relatively few studies from the United Kingdom, there is consensus that students enjoy the incorporation of ultrasound practice and believe it complements existing teaching, especially in a small group setting.

Impact of Peripheral Nerve Block Technique on Incidence of Phrenic Nerve Palsy in Shoulder Surgery.

Peripheral nerve blocks are an increasingly common method of providing postoperative analgesia for shoulder surgeries. However, the standard technique, the interscalene block (ISB), inevitably causes hemidiaphragmatic paresis (HDP), secondary to phrenic nerve palsy. This can cause morbidity in patients with preexisting respiratory compromise, prompting investigation into alternative "phrenic-sparing" nerve blocks. The aim of this review was to give an overview of these blocks and critically evaluate the current literature to determine if any are suitable replacements for ISB. The incidence of HDP and analgesic efficacy were considered. We queried four electronic databases and one register. Twenty-eight original articles were selected for review. The use of ultrasound guidance, lower volumes of local anaesthetic (LA), and injection 4 mm outside the brachial plexus fascia reduced HDP incidence for the ISB; however, no single modification did so sufficiently. While the anterior suprascapular nerve block (SSNB) showed comparable analgesic effects to the ISB, HDP prevalence was also high. The posterior SSNB produced consistently low HDP incidences but also inferior analgesia to ISB, except when combined with an infraclavicular brachial plexus block. The superior trunk block (STB) provided equivalent analgesia to the ISB while reducing HDP incidence, but not significantly. Lower LA volumes consistently led to lower HDP incidence across all blocks, likely due to a reduced ability to spread to the phrenic nerve. Further investigation into the minimum effective volumes of the extrafascial ISB, anterior SSNB, STB, and combined posterior SSNB with infraclavicular block is warranted to determine if any of these blocks can successfully balance HDP prevention with analgesic efficacy.

Bidirectional TRP/L Type Ca2+ Channel/RyR/BKCa Molecular and Functional Signaloplex in Vascular Smooth Muscles.

TRP channels are expressed both in vascular myocytes and endothelial cells, but knowledge of their operational mechanisms in vascular tissue is particularly limited. Here, we show for the first time the biphasic contractile reaction with relaxation followed by a contraction in response to TRPV4 agonist, GSK1016790A, in a rat pulmonary artery preconstricted with phenylephrine. Similar responses were observed both with and without endothelium, and these were abolished by the TRPV4 selective blocker, HC067047, confirming the specific role of TRPV4 in vascular myocytes. Using selective blockers of BKCa and L-type voltage-gated Ca2+ channels (CaL), we found that the relaxation phase was inducted by BKCa activation generating STOCs, while subsequent slowly developing TRPV4-mediated depolarisation activated CaL, producing the second contraction phase. These results are compared to TRPM8 activation using menthol in rat tail artery. Activation of both types of TRP channels produces highly similar changes in membrane potential, namely slow depolarisation with concurrent brief hyperpolarisations due to STOCs. We thus propose a general concept of bidirectional TRP-CaL-RyR-BKCa molecular and functional signaloplex in vascular smooth muscles. Accordingly, both TRPV4 and TRPM8 channels enhance local Ca2+ signals producing STOCs via TRP-RyR-BKCa coupling while simultaneously globally engaging BKCa and CaL channels by altering membrane potential.

Ultrasound imaging in teaching cardiovascular physiology: disruption and challenge to foster learning.

This work extends previously described applications of ultrasound technology in illustrating cardiovascular phenomena to investigation of learning effectiveness. To this end, learning in ultrasound-enhanced classes was assessed by quantifying the improvement in single best answer (SBA) exams conducted before and after an ultrasound practical class. This improvement was then compared to that seen in the same SBA exams conducted in matched groups that undertook similar classes conducted without ultrasound equipment. The SBA exams were designed to include questions that directly related to the phenomena being investigated in the practical classes as well as other "filler" questions to disguise the intent of the exam and ensure that standards of physiology knowledge were similar between the two groups. Any small statistically significant gains in performance observed between the two groups were confounded by differences in baseline (pretest) performance between the groups. These results contradict our previous work, which showed that self-reported measures of learning increased after ultrasound classes. It may be optimistic to expect improvements in deep learning and test performance immediately after even the most effective educational intervention. Direct measurement of the phenomena that bring about deep, long-term learning in classes remains problematic. Notwithstanding this, there is much evidence for the value of enhancing physiology learning by providing varying contexts in the physical, semantic, and cognitive domains. Ultrasound technology is a cheap and effective means of providing such context in physiology practical classes.NEW & NOTEWORTHY This work compares learning in cardiovascular physiology classes enhanced by using cheap ultrasound equipment with learning in comparable control classes without ultrasound. Performance improvement in single best answer tests between pre- and postclass tests were compared for the ultrasound and control classes, with little difference shown between the two classes. We question whether it is appropriate to measure deep learning after 2-h classes or whether other, phenomenological, qualitative measures of educational effectiveness would be better.

Snapshot of ultrasound imaging in basic anatomy and physiology teaching in the United Kingdom and Republic of Ireland: perceptions, obstacles, and solutions.

We have used ultrasound imaging and technology as a tool for nonclinical teaching of basic physiological concepts for several years and are aware anecdotally that only a few others in the United Kingdom and Republic of Ireland (UK/ROI) are also using ultrasound with this intention in physiology and anatomy teaching. To better understand what areas ultrasound is used for by others, along with what barriers might exist to its use, we reached out to colleagues in UK/ROI institutions instructing on anatomy and physiology courses by asking them to complete a survey regarding their experiences. Relatively few institutions (9%) reported using the technology in this way but covered physiology and anatomy teaching in most major body systems. The perception of responding educators overall is that, overwhelmingly, ultrasound offers a useful addition to the teaching of physiology and anatomy and is very popular with students. Barriers to its implementation were identified, including unfamiliarity with equipment and potential uses. Lack of funding for equipment and staff, issues with class sizes, and lack of curriculum time were also identified. Despite these potential impediments, most nonusers were interested in finding out about the uses of ultrasound as a teaching tool. We conclude that the teaching community would benefit from wider dissemination of local practices.NEW & NOTEWORTHY We surveyed UK and Republic of Ireland institutions to establish the extent of ultrasound use in teaching undergraduate modules with significant anatomy or physiology content. Responses indicate that although ultrasound is used for a wide variety of systems, only a small proportion of courses use ultrasound for teaching. There is widespread interest in its use, with the main barriers being unfamiliarity with potential uses and the technology. We endorse further dissemination of this teaching practice.

Brachial artery blood flow by vascular ultrasound in education.

There is extensive and increasing use of ultrasound in medical care and scientific research, so it is important that the technique, indication, and interpretation of ultrasound investigations are included in medical and biological education. Applications of ultrasound in medical care and education employ not only noninvasive imaging of structure but also the evaluation of organ function. Vascular ultrasound is one such application that has been hitherto relatively neglected in physiology education. The techniques of vascular ultrasound and the physiological regulation of human limb blood flow are reviewed to inform students and curriculum designers. Emphasis is placed on the value of converting velocity measurement by ultrasound to volumetric flow and on the mechanisms involved in rapidly changing flows with interventions. Live collection of real data by ultrasound can show macrovascular and microvascular features of vascular physiology. Macrovascular features include imaging and flow velocity profiles. Microvascular perfusion studies show conductance changes with interventions such as exercise and ischemia. Vascular ultrasound offers exciting opportunities for undergraduate research projects using human subjects. The literature is interesting and, though complex, offers excellent educational experience, with scope for the development of critical thinking and meaningful original research.NEW & NOTEWORTHY Ultrasound imaging has emergent prominence in clinical investigation and education. Vascular ultrasound also evaluates function. Simple methods are described that enable the application of basic ultrasound principles to the measurement of velocity and, importantly, to calculate absolute volumetric blood flow. These methods should be useful in undergraduate and graduate education, with application in clinical practice and research.

Feeder-Cell-Free and Serum-Free Expansion of Natural Killer Cells Using Cloudz Microspheres, G-Rex6M, and Human Platelet Lysate.

The versatility of natural killer cells has ignited growing interest in their therapeutic use for cancer and other immunotherapy treatments. However, NK cells compose a small portion of peripheral blood mononuclear cells (5%-20% of PBMCs) and clinical doses require billions of cells. Manufacturing suitable doses of NK cells remains a major challenge for NK immunotherapy. The current standard for expanding NK cells relies on feeder cells and fetal bovine serum to achieve large expansion, but both encounter regulatory concerns. We developed NK Cloudz, a dissolvable polymer-based microsphere platform, as an alternative to a feeder cell approach to expand NK cells. We demonstrated that a combination of NK Cloudz, a G-Rex6M culture vessel, and GMP Human Platelet Lysate expanded NK cells 387 ± 100-fold in 10 days from a PBMC starting population. The NK purity, viability, and cytotoxicity were similar to both a feeder cell protocol and an FBS-based protocol. Additionally, we found no significant differences between FBS and GMP Human Platelet Lysate and concluded that platelet lysate is a good xeno-free alternative to FBS for NK expansion. Overall, we demonstrated a feeder-cell-free and FBS-free protocol that leverages NK Cloudz as a promising step toward a commercial GMP manufacturing method to expand NK cells for therapeutic use.

Using two-dimensional ultrasound imaging to examine venous pressure.

Ultrasound imaging is being used increasingly to aid in the teaching of human physiology and anatomy. Here we describe how its use can be integrated into the teaching of concepts surrounding venous circulation, specifically 1) venous valves and the muscle pump, 2) the effects of hydrostatic pressure on venous pressure, and 3) central venous pressure. The imaging procedures described are relatively simple but add a dimension that helps deliver the teaching points clearly and is enjoyable for students. They also aid in the link of basic physiology to clinical aspects of venous circulatory physiology.

Understanding basic vein physiology and venous blood pressure through simple physical assessments.

An understanding of the complexity of the cardiovascular system is incomplete without a knowledge of the venous system. It is important for students to understand that, in a closed system, like the circulatory system, changes to the venous side of the circulation have a knock-on effect on heart function and the arterial system and vice versa. Veins are capacitance vessels feeding blood to the right side of the heart. Changes in venous compliance have large effects on the volume of blood entering the heart and hence cardiac output by the Frank-Starling Law. In healthy steady-state conditions, venous return has to equal cardiac output, i.e., the heart cannot pump more blood than is delivered to it. A sound understanding of the venous system is essential in understanding how changes in cardiac output occur with changes in right atrial pressure or central venous pressure, and the effect these changes have on arterial blood pressure regulation. The aim of this paper is to detail simple hands-on physiological assessments that can be easily undertaken in the practical laboratory setting and that illustrate some key functions of veins. Specifically, we illustrate that venous valves prevent the backflow of blood, that venous blood pressure increases from the heart to the feet, that the skeletal muscle pump facilitates venous return, and we investigate the physiological and clinical significance of central venous pressure and how it may be assessed.

The Effect of Electrospun Fiber Diameter on Astrocyte-Mediated Neurite Guidance and Protection.

The topography of electrospun fiber scaffolds modifies astrocytes toward in vivo-like morphologies and behaviors. However, little is known about how electrospun fiber diameter influences astrocyte behavior. In this work, aligned fibers with two distinct nanoscale fiber diameters (808 and 386 nm) were prepared, and the astrocyte response was measured over time. Astrocytes on the large diameter fibers showed significantly increased elongation as early as 2 h after seeding and remained significantly more elongated for up to 4 days compared to those on small diameter fibers. Astrocytes extending along larger diameter fibers were better equipped to support long neurite outgrowth from dorsal root ganglia neurons, and neurite outgrowth along these astrocytes was less branched than outgrowth along astrocytes cultured on small diameter fibers. The differences in astrocyte shape observed on the small or large diameter fibers did not translate into differences in GLT-1, GFAP, or GLAST protein expression. Thus, different fiber diameters were unable to influence astrocyte protein expression uniquely. Nevertheless, astrocytes cultured in either small or large fibers significantly increased their expression of GLT-1 compared to astrocytes cultured on nonfiber (film) controls. Fibrous-induced increases in astrocyte GLT-1 expression protected astrocyte/neuron cocultures from toxicity generated by high extracellular glutamate. Alternatively, astrocytes/neurons cultured on films were less able to protect these cells from culture conditions consisting of high glutamate levels. Biomaterials, such as the fibrous materials presented here, may help stimulate astrocytes to increase GLT-1 expression and uptake more glutamate, since astrocytes are less likely to uptake glutamate in neurodegenerative pathologies or following central nervous system injury.

Multi-modal characterization of polymeric gels to determine the influence of testing method on observed elastic modulus.

Demand for materials that mechanically replicate native tissue has driven development and characterization of various new biomaterials. However, a consequence of materials and characterization technique diversity is a lack of consensus within the field, with no clear way to compare values measured via different modalities. This likely contributes to the difficulty in replicating findings across the research community; recent evidence suggests that different modalities do not yield the same mechanical measurements within a material, and direct comparisons cannot be made across different testing platforms. Herein, we examine whether "material properties" are characterization modality-specific by analyzing the elastic moduli determined by five typical biomaterial mechanical characterization techniques: unconfined-compression, tensiometry, rheometry, and micro-indentation at the macroscopic level, and microscopically using nanoindentation. These analyses were performed in two different polymeric gels frequently used for biological applications, polydimethylsiloxane (PDMS) and agarose. Each was fabricated to span a range of moduli, from physiologic to supraphysiologic values. All five techniques identified the same overall trend within each material group, supporting their ability to appreciate relative moduli differences. However, significant differences were found across modalities, illustrating a difference in absolute moduli values, and thereby precluding direct comparison of measurements from different characterization modalities. These observed differences may depend on material compliance, viscoelasticity, and microstructure. While determining the underlying mechanism(s) of these differences was beyond the scope of this work, these results demonstrate how each modality affects the measured moduli of the same material, and the sensitivity of each modality to changes in sample material composition.

Exploring the effects of electrospun fiber surface nanotopography on neurite outgrowth and branching in neuron cultures.

Three aligned, electrospun fiber scaffolds with unique surface features were created from poly-L-lactic acid (PLLA). Fibers without surface nanotopography (smooth fibers), fibers with surface divots (shallow pits), and fibers with surface pits (deeper pits) were fabricated, and fiber alignment, diameter, and density were characterized using scanning electron microscopy (SEM). Whole dorsal root ganglia (DRG) were isolated from rats and placed onto uncoated fibers or fibers coated with laminin. On uncoated fibers, neurite outgrowth was restricted by fibers displaying divoted or pitted nanotopography when compared to neurite outgrowth on smooth fibers. However, neurites extending from whole DRG cultured on laminin-coated fibers were not restricted by divoted or pitted surface nanotopography. Thus, neurites extending on laminin-coated fibers were able to extend long neurites even in the presence of surface divots or pits. To further explore this result, individual neurons isolated from dissociated DRG were seeded onto laminin-coated smooth, pitted, or divoted fibers. Interestingly, neurons on pitted or divoted fibers exhibited a 1.5-fold increase in total neurite length, and a 2.3 or 2.7-fold increase in neurite branching compared to neurons on smooth fibers, respectively. Based on these findings, we conclude that fiber roughness in the form of pits or divots can promote extension and branching of long neurites along aligned electrospun fibers in the presence of an extracellular matrix protein coating. Thus, aligned, electrospun fibers can be crafted to not only direct the extension of axons but to induce unique branching morphologies.

Muscle hypotrophy, not inhibition, is responsible for quadriceps weakness during rehabilitation after anterior cruciate ligament reconstruction.

PURPOSE: Quadriceps weakness is common after anterior cruciate ligament reconstruction (ACLR). Limited neuromuscular activation may have a role in the weakness. The purpose of this study was to use peripheral magnetic stimulation to measure changes in quadriceps inhibition in patients during rehabilitation from ACLR. METHODS: Ten patients (7M/3F; age 35 ± 8 years; BMI 26.0 ± 4.8 kg/m2) who had ACLR with patellar tendon autograft were recruited. At 3 and 6 months postoperatively, patients' knee extension peak torque was measured during maximum voluntary isometric contraction (MVIC), magnetic stimulation-evoked contraction, and MVIC augmented with superimposed burst magnetic stimulation to the femoral nerve. All tests were done bilaterally at 30° and 65° of knee flexion on a dynamometer. Central activation ratio was calculated by dividing the peak torque before stimulation by peak torque after stimulation. RESULTS: Patients had marked deficits in MVIC, with improvement from 3 to 6 months that was more apparent at 65° versus 30° (P < 0.05). There was significant deficit in stimulation-evoked torque on the involved side that diminished over time, and this change occurred differently between the two angles (P < 0.05). Central activation ratio was lower on the involved side versus the noninvolved side and this effect was more prominent at 3 versus 6 months: combining the angles, mean central activation ratio on the involved and noninvolved sides, respectively, was 91.4 ± 7.6% and 97.5 ± 5.3% at 3 months, and 93.0 ± 7.8% and 95.8 ± 6.8% at 6 months. CONCLUSIONS: At 3 and 6 months after ACLR, there were significant deficits in quadriceps strength and activation. Quadriceps activation levels were high (> 90%) for both sides at both time points. The substantial strength deficits at this postoperative period may be largely due to muscle atrophy with limited contribution from central inhibition. Rehabilitation interventions to normalize quadriceps strength should emphasize hypertrophic stimuli as opposed to neuromuscular activation strategies. LEVEL OF EVIDENCE: II, prospective cohort study.

Injectable, Magnetically Orienting Electrospun Fiber Conduits for Neuron Guidance.

Magnetic electrospun fibers are of interest for minimally invasive biomaterial applications that also strive to provide cell guidance. Magnetic electrospun fibers can be injected and then magnetically positioned in situ, and the aligned fiber scaffolds provide consistent topographical guidance to cells. In this study, magnetically responsive aligned poly-l-lactic acid electrospun fiber scaffolds were developed and tested for neural applications. Incorporating oleic acid-coated iron oxide nanoparticles significantly increased neurite outgrowth, reduced the fiber alignment, and increased the surface nanotopography of the electrospun fibers. After verifying neuron viability on two-dimensional scaffolds, the system was tested as an injectable three-dimensional scaffold. Small conduits of aligned magnetic fibers were easily injected in a collagen or fibrinogen hydrogel solution and repositioned using an external magnetic field. The aligned magnetic fibers provided internal directional guidance to neurites within a three-dimensional collagen or fibrin model hydrogel, supplemented with Matrigel. Neurites growing from dorsal root ganglion explants extended 1.4-3× farther on the aligned fibers compared with neurites extending in the hydrogel alone. Overall, these results show that magnetic electrospun fiber scaffolds can be injected and manipulated with a magnetic field in situ to provide directional guidance to neurons inside an injectable hydrogel. Most importantly, this injectable guidance system increased both neurite alignment and neurite length within the hydrogel scaffold.

Increased SOX9 Expression in Premalignant and Malignant Pancreatic Neoplasms.

BACKGROUND: SOX9, a progenitor cell marker, is important for pancreatic ductal development. Our goal was to examine SOX9 expression differences in intraductal papillary mucinous neoplasms (IPMNs) and ductal adenocarcinoma (PDAC) compared with benign pancreatic duct (BP). METHODS: SOX9 expression was evaluated by immunohistochemistry performed on 93 specimens: 37 BP, 24 low grade (LG) IPMN, 12 high grade (HG) IPMN, and 20 PDAC. A linear mixed-effects model was used to compare the percentage of cells expressing SOX9 by specimen type. A separate linear mixed-effects model evaluated differences in SOX9 expression by staining intensity in pancreatic epithelial cells. RESULTS: Nuclear SOX9 expression was detected in the epithelial cells of 98% HG IPMN, 93% LG IPMN, 83% PDAC, and 60% BP. Compared with BP, SOX9 was expressed from a significantly greater percentage of cells in LG IMPN, HG IMPN, and PDAC (p < 0.001 for each). BP and PDAC showed greater variability in SOX9 expression in epithelial cells compared with IPMNs which showed strong, homogenous SOX9 expression in almost all cells. Compared with BP, both LG and HG IPMN showed significantly greater SOX9 expression (p < 0.001 for each), but there was no significant difference in SOX9 expression between LG and HG IPMN (p > 0.05). PDAC had significantly higher expression of SOX9 compared with BP but significantly lower SOX9 expression compared with LG or HG IPMN (p < 0.001 for each). CONCLUSIONS: IPMNs demonstrated the highest expression levels of SOX9. SOX9 expression in BP and PDAC demonstrated much more heterogeneity compared with the strong, uniform expression in IPMN.

Electrospun fiber surface nanotopography influences astrocyte-mediated neurite outgrowth.

Aligned, electrospun fiber scaffolds provide topographical guidance for regenerating neurons and glia after central nervous system injury. To date, no study has explored how fiber surface nanotopography affects astrocyte response to fibrous scaffolds. Astrocytes play important roles in the glial scar, the blood brain barrier, and in maintaining homeostasis in the central nervous system. In this study, electrospun poly L-lactic acid fibers were engineered with smooth, pitted, or divoted surface nanotopography. Cortical or spinal cord primary rat astrocytes were cultured on the surfaces for either 1 or 3 d to examine the astrocyte response over time. The results showed that cortical astrocytes were significantly shorter and broader on the pitted and divoted fibers compared to those on smooth fibers. However, spinal cord astrocyte morphology was not significantly altered by the surface features. These findings indicate that astrocytes from unique anatomical locations respond differently to the presence of nanotopography. Western blot results show that the differences in morphology were not associated with significant changes in glial fibrillary acidicprotein (GFAP) or vinculin in either astrocyte population, suggesting that surface pits and divots do not induce a reactive phenotype in either cortical or spinal cord astrocytes. Finally, astrocytes were co-cultured with dorsal root ganglia to determine how the surfaces affected astrocyte-mediated neurite outgrowth. Astrocytes cultured on the fibers for shorter periods of time (1 d) generally supported longer neurite outgrowth. Pitted and divoted fibers restricted spinal cord astrocyte-mediated neurite outgrowth, while smooth fibers increased 3 d spinal cord astrocyte-mediated neurite outgrowth. In total, fiber surface nanotopography can influence astrocyte elongation and influence the capability of astrocytes to direct neurites. Therefore, fiber surface characteristics should be carefully controlled to optimize astrocyte-mediated axonal regeneration.

Cell death as a trigger for morphogenesis.

The complex morphologies observed in many biofilms play a critical role in the survival of these microbial communities. Recently, the formation of wrinkles has been the focus of many studies aimed at finding fundamental information on morphogenesis during development. While the underlying genetic mechanisms of wrinkling are not well-understood, recent discoveries have led to the counterintuitive idea that wrinkle formation is triggered by localized cell death. This work examines the hypothesis that the material properties of a biofilm both power and control wrinkle formation within biofilms in response to localized cell death. Using an agent-based model and a high-performance platform (Biocellion), we built a model that qualitatively reproduced wrinkle formation in biofilms due to cell death. Through the use of computational simulations, we determined important relationships between cellular level mechanical interactions and changes in colony morphology. These simulations were also used to identify significant cellular interactions that are required for wrinkle formation. These results are a first step towards more comprehensive models that, in combination with experimental observations, will improve our understanding of the morphological development of bacterial biofilms.

Reducing low birth weight: prioritizing action to address modifiable risk factors.

Background: Low birth weight (LBW) affects 6.9% of all UK births and has remained largely unchanged for many years. The United Nations and the World Health Assembly have set targets to substantially reduce global incidence. Understanding the contribution of modifiable risk factors to the burden of LBW is required to ensure appropriate interventions are in place to achieve this reduction. Methods: Data from published studies on the risks from key modifiable factors were used alongside prevalence data from the Welsh population to calculate the population attributable risk for each factor individually and in combination. Results: Fourteen risk factors accounted for nearly half of LBW births, and 60% of those to younger mothers (<25 years). Tobacco smoke exposure was the largest contributor. We estimated that smoking in pregnancy was a factor in one in eight LBW births, increasing to one in five for women aged under 25. Conclusions: Risk factors are interrelated and inequitably distributed within the population. Exposure to one factor increases the likelihood of exposure to a constellation of factors further increasing risk. Action to address LBW must consider groups where the risk factors are most prevalent and address these risk factors together using multi-component interventions.

Functional Outcomes After Double-Row Versus Single-Row Rotator Cuff Repair: A Prospective Randomized Trial.

BACKGROUND: The functional benefits of double-row (DR) versus single-row (SR) rotator cuff repair are not clearly established. PURPOSE: To examine the effect of DR versus SR rotator cuff repair on functional outcomes and strength recovery in patients with full-thickness tears. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: Forty-nine patients were randomized to DR or SR repairs; 36 patients (13 women, 23 men; mean age, 62 ± 7 years; 20 SR, 16 DR) were assessed at a mean 2.2 ± 1.6 years after surgery (range, 1-7 years; tear size: 17 medium, 13 large, 9 massive). The following data were recorded prior to surgery and at follow-up: Penn shoulder score, American Shoulder and Elbow Surgeons (ASES), and Simple Shoulder Test (SST) results; range of motion (ROM) for shoulder flexion, external rotation (ER) at 0° and 90° of abduction, and internal rotation (IR) at 90° of abduction; and shoulder strength (Lafayette manual muscle tester) in empty- and full-can tests, abduction, and ER at 0° of abduction. Treatment (SR vs DR) × time (pre- vs postoperative) mixed-model analysis of variance was used to assess the effect of rotator cuff repair. RESULTS: Rotator cuff repair markedly improved Penn, ASES, and SST scores (P < .001), with similar improvement between SR and DR repairs (treatment × time, P = .38-.10) and excellent scores at follow-up (DR vs SR: Penn, 91 ± 11 vs 92 ± 11 [P = .73]; ASES, 87 ± 12 vs 92 ± 12 [P = .21]; SST, 11.4 ± 1.0 vs 11.3 ± 1.0 [P = .76]). Patients with DR repairs lost ER ROM at 0° of abduction (preoperative to final follow-up, 7° ± 10° loss [P = .013]). ER ROM did not significantly change with SR repair (5° ± 14° gain, P = .16; treatment by time, P = .008). This effect was not apparent for ER ROM at 90° of abduction (treatment × time, P = .26). IR ROM improved from preoperative to final follow-up (P < .01; SR, 17° ± 27°; DR, 7° ± 21°; treatment × time, P = .23). Rotator cuff repair markedly improved strength in empty-can (54%), full-can (66%), abduction (47%), and ER (54%) strength (all P < .001), with no difference between SR and DR repairs (P = .23-.75). All clinical tests with the exception of the lift-off test were normalized at follow-up (P < .05). CONCLUSION: Outcomes were not different between SR or DR repair, with generally excellent outcomes for both groups. Rotator cuff repair and subsequent rehabilitation markedly improved shoulder strength.

Ion channel mechanisms of rat tail artery contraction-relaxation by menthol involving, respectively, TRPM8 activation and L-type Ca2+ channel inhibition.

Transient receptor potential melastatin 8 (TRPM8) is the principal cold and menthol receptor channel. Characterized primarily for its cold-sensing role in sensory neurons, it is expressed and functional in several nonneuronal tissues, including vasculature. We previously demonstrated that menthol causes variable mechanical responses (vasoconstriction, vasodilatation, or biphasic reactions) in isolated arteries, depending on vascular tone. Here we aimed to dissect the specific ion channel mechanisms and corresponding Ca2+ signaling pathways underlying such complex responses to menthol and other TRPM8 ligands in rat tail artery myocytes using patch-clamp electrophysiology, confocal Ca2+ imaging, and ratiometric Ca2+ recording. Menthol (300 µM, a concentration typically used to induce TRPM8 currents) strongly inhibited L-type Ca2+ channel current (L-ICa) in isolated myocytes, especially its sustained component, most relevant for depolarization-induced vasoconstriction. In contraction studies, with nifedipine present (10 µM) to abolish L-ICa contribution to phenylephrine (PE)-induced vasoconstrictions of vascular rings, a marked increase in tone was observed with menthol, similar to resting (i.e., without α-adrenoceptor stimulation by PE) conditions, when L-type channels were mostly deactivated. Menthol-induced increases in PE-induced vasoconstrictions could be inhibited both by the TRPM8 antagonist AMTB (thus confirming the specific role of TRPM8) and by cyclopiazonic acid treatment to deplete Ca2+ stores, pointing to a major contribution of Ca2+ release from the sarcoplasmic reticulum in these contractile responses. Immunocytochemical analysis has indeed revealed colocalization of TRPM8 and InsP3 receptors. Moreover, menthol Ca2+ responses, which were somewhat reduced under Ca2+-free conditions, were strongly reduced by cyclopiazonic acid treatment to deplete Ca2+ store, whereas caffeine-induced Ca2+ responses were blunted in the presence of menthol. Finally, two other common TRPM8 agonists, WS-12 and icilin, also inhibited L-ICa With respect to L-ICa inhibition, WS-12 is the most selective agonist. It augmented PE-induced contractions, whereas any secondary phase of vasorelaxation (as with menthol) was completely lacking. Thus TRPM8 channels are functionally active in rat tail artery myocytes and play a distinct direct stimulatory role in control of vascular tone. However, indirect effects of TRPM8 agonists, which are unrelated to TRPM8, are mediated by inhibition of L-type Ca2+ channels and largely obscure TRPM8-mediated vasoconstriction. These findings will promote our understanding of the vascular TRPM8 role, especially the well-known hypotensive effect of menthol, and may also have certain translational implications (e.g., in cardiovascular surgery, organ storage, transplantation, and Raynaud's phenomenon).